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Yang X, Yao K, Zhang M, Zhang W, Zu H. New insight into the role of altered brain cholesterol metabolism in the pathogenesis of AD: A unifying cholesterol hypothesis and new therapeutic approach for AD. Brain Res Bull 2025; 224:111321. [PMID: 40164234 DOI: 10.1016/j.brainresbull.2025.111321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/16/2025] [Accepted: 03/24/2025] [Indexed: 04/02/2025]
Abstract
The dysregulation of cholesterol metabolism homeostasis has been universally suggested in the aeotiology of Alzheimer's disease (AD). Initially, studies indicate that alteration of serum cholesterol level might contribute to AD. However, because blood-brain barrier impedes entry of plasma cholesterol, brain cells are not directly influenced by plasma cholesterol. Furthermore, mounting evidences suggest a link between alteration of brain cholesterol metabolism and AD. Interestingly, Amyloid-β proteins (Aβ) can markedly inhibit cellular cholesterol biosynthesis and lower cellular cholesterol content in cultured cells. And Aβ overproduction/overload induces a significant decrease of brain cellular cholesterol content in familial AD (FAD) animals. Importantly, mutations or polymorphisms of genes related to brain cholesterol transportation, such as ApoE4, ATP binding cassette (ABC) transporters, low-density lipoprotein receptor (LDLR) family and Niemann-Pick C disease 1 or 2 (NPC1/2), obviously lead to decreased brain cholesterol transport, resulting in brain cellular cholesterol loss, which could be tightly associated with AD pathological impairments. Additionally, accumulating data show that there are reduction of brain cholesterol biosynthesis and/or disorder of brain cholesterol trafficking in a variety of sporadic AD (SAD) animals and patients. Collectively, compelling evidences indicate that FAD and SAD could share one common and overlapping neurochemical mechanism: brain neuronal/cellular cholesterol deficiency. Therefore, accumulated evidences strongly support a novel hypothesis that deficiency of brain cholesterol contributes to the onset and progression of AD. This review highlights the pivotal role of brain cholesterol deficiency in the pathogenesis of AD. The hypothesis offers valuable insights for the future development of AD treatment.
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Affiliation(s)
- Xiaobo Yang
- Department of Neurology, Jinshan Hospital affiliated to Fudan University, Shanghai 201508, China; Department of Neurology, Shanghai Xuhui Central Hospital, Fudan University, Shanghai 200237, China
| | - Kai Yao
- Department of Neurology, Jinshan Hospital affiliated to Fudan University, Shanghai 201508, China
| | - Mengqi Zhang
- Department of Neurology, Jinshan Hospital affiliated to Fudan University, Shanghai 201508, China
| | - Wenbin Zhang
- Department of Neurology, Jinshan Hospital affiliated to Fudan University, Shanghai 201508, China
| | - Hengbing Zu
- Department of Neurology, Jinshan Hospital affiliated to Fudan University, Shanghai 201508, China.
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Xu M, Wang L, Meng Y, Kang G, Jiang Q, Yan T, Che F. The role of lipid metabolism in cognitive impairment. ARQUIVOS DE NEURO-PSIQUIATRIA 2025; 83:1-13. [PMID: 39814004 PMCID: PMC11735072 DOI: 10.1055/s-0044-1792097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 07/27/2024] [Indexed: 01/18/2025]
Abstract
Alzheimer's disease (AD), diabetic cognitive impairment (DCI), and vascular dementia (VD) are considered the most common causes of severe cognitive impairment in clinical practice. Numerous factors can influence their progression, and many studies have recently revealed that metabolic disorders play crucial roles in the progression of cognitive impairment. Mounting evidence indicate that the regulation of lipid metabolism is a major factor in maintaining brain homeostasis. Generally, abnormalities in lipid metabolism can affect amyloid-beta (Aβ) deposition, tau hyperphosphorylation, and insulin resistance through lipid metabolic signaling cascades; affect the neuronal membrane structure, neurotransmitter synthesis and release; and promote synapse growth, which can impact neural signal transmission and exacerbate disease progression in individuals with cognitive impairment, including AD, DCI, and VD. Moreover, apolipoprotein E (APOE), a key protein in lipid transport, is involved in the occurrence and development of the aforementioned diseases by regulating lipid metabolism. The present article mainly discusses how lipid metabolic disorders in the brain microenvironment are involved in regulating the progression of cognitive impairment, and it explores the regulatory effects of targeting the key lipid transport protein APOE in the context of the role of lipid metabolism in the common pathogenesis of three diseases-Aβ deposition, tau hyperphosphorylation, and insulin resistance-which will help elucidate the potential of targeting lipid metabolism for the treatment of cognitive impairment.
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Affiliation(s)
- Meifang Xu
- Second Medical University, School of Clinical Medicine, Weifang Shandong Province, China.
- Linyi People's Hospital, Department of Neurology, Linyi Shandong Province, China.
| | - Liyuan Wang
- Second Medical University, School of Clinical Medicine, Weifang Shandong Province, China.
| | - Yun Meng
- Linyi People's Hospital, Department of Neurology, Linyi Shandong Province, China.
| | - Guiqiong Kang
- Guangzhou University of Chinese Medicine, Linyi People's Hospital, Linyi Shandong Province, China.
| | - Qing Jiang
- Harbin Medical University, First Affiliated Hospital, Department of Neurosurgery, Harbin Heilongjiang Province, China.
- Key Colleges and Universities, Laboratory of Neurosurgery, Harbin Heilongjiang Province, China.
| | - Tao Yan
- Linyi People's Hospital, Department of Neurology, Linyi Shandong Province, China.
| | - Fengyuan Che
- Second Medical University, School of Clinical Medicine, Weifang Shandong Province, China.
- Linyi People's Hospital, Department of Neurology, Linyi Shandong Province, China.
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Pettigrew C, Soldan A, Wang J, Hohman T, Dumitrescu L, Albert M, Blennow K, Bittner T, Moghekar A. Plasma biomarker trajectories: Impact of AD genetic risk and clinical progression. ALZHEIMER'S & DEMENTIA (AMSTERDAM, NETHERLANDS) 2025; 17:e70081. [PMID: 40151521 PMCID: PMC11947672 DOI: 10.1002/dad2.70081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/20/2024] [Accepted: 01/03/2025] [Indexed: 03/29/2025]
Abstract
INTRODUCTION We examined long-term plasma biomarker trajectories among participants who were cognitively unimpaired and primarily middle aged at baseline and whether trajectories differed by Alzheimer's disease (AD) genetic risk and among those who developed cognitive impairment. METHODS Plasma amyloid beta (Aβ)42/Aβ40, phosphorylated tau (p-tau)181, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells, and chitinase 3-like protein 1 were measured longitudinally in 177 BIOCARD participants (M baseline age = 57.7 years; M follow-up = 15.8 years), including 57 who developed cognitive impairment. Measures of AD genetic risk included apolipoprotein E (APOE) ε4 and an AD polygenic risk score (AD-PRS). RESULTS Compared to non-carriers, APOE ε4 carriers had lower Aβ42/Aβ40 and greater longitudinal increases in p-tau181 and GFAP; in contrast, the AD-PRS (excluding the APOE region) was associated with greater declines in Aβ42/Aβ40 among APOE ε4 non-carriers. Rates of increase in p-tau181, NfL, and GFAP were greater among those who later developed cognitive impairment. DISCUSSION Monitoring changes in plasma p-tau181, NfL, and GFAP may be particularly informative during preclinical AD. Highlights We examined plasma biomarker changes in cognitively normal individuals over 15.8 years.Apolipoprotein E (APOE) ε4 was related to lower amyloid beta (Aβ)42/Aβ40 and greater increases in phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP).In APOE ε4 non-carriers, higher Alzheimer's disease (AD) polygenic risk score was related to greater Aβ42/Aβ40 declines.P-tau181, NfL, and GFAP increases were greater among those who progressed to mild cognitive impairment.Results highlight the predictive value of plasma biomarkers during preclinical AD.
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Affiliation(s)
- Corinne Pettigrew
- Department of NeurologyThe Johns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Anja Soldan
- Department of NeurologyThe Johns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Jiangxia Wang
- Department of BiostatisticsThe Johns Hopkins Bloomberg School of Public HealthBaltimoreMarylandUSA
| | - Timothy Hohman
- Department of NeurologyVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Logan Dumitrescu
- Department of NeurologyVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Marilyn Albert
- Department of NeurologyThe Johns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Kaj Blennow
- Institute of Neuroscience and PhysiologyUniversity of GothenburgMölndalSweden
- Clinical Neurochemistry LabSahlgrenska University HospitalMölndalSweden
- Paris Brain InstituteICMPitié‐Salpêtrière HospitalSorbonne UniversityParisFrance
| | - Tobias Bittner
- F. Hoffmann‐LaRoche AGBaselSwitzerland
- Genentech Inc.South San FranciscoCaliforniaUSA
| | - Abhay Moghekar
- Department of NeurologyThe Johns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - The BIOCARD Study Team
- Department of NeurologyThe Johns Hopkins University School of MedicineBaltimoreMarylandUSA
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Kshirsagar S, Islam MA, Reddy AP, Reddy PH. Cell culture research in aging and Alzheimer's disease: The strategic use/reuse of untreated controls and savings people's tax dollars. J Alzheimers Dis Rep 2025; 9:25424823241310716. [PMID: 40034533 PMCID: PMC11864248 DOI: 10.1177/25424823241310716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/04/2024] [Indexed: 03/05/2025] Open
Abstract
Cell culture is an essential tool in both fundamental and translational research, particularly for understanding complex diseases like Alzheimer's disease (AD). The use of cell lines provides the advantage of genetic homogeneity, ensuring reproducible and consistent results. This article explores the application of mammalian cell cultures to model AD, focusing on the transfection of cells with key genes associated with the disease to replicate the cellular environment of AD. It explains various transfection methods and challenges related to the process. These models offer a robust platform for investigating cellular biology, molecular pathways, physiological processes, and drug discovery efforts. A range of assays, including RT-PCR, western blotting, ELISA, mitochondrial respiration, and reactive oxygen species analysis, are employed to assess the impact of genetic modifications on cellular functions and to screen potential AD therapies. Researchers often design experiments with multiple variables such as genetic modifications, chemical treatments, or time points, paired with positive and negative controls. By using a consistent control group across all conditions and under identical experimental conditions, researchers can minimize variability and enhance data reproducibility. This approach is particularly valuable in AD research, where small experimental differences can significantly influence outcomes. Using a shared control group ensures data comparability across experiments, saving time and resources by eliminating redundant control tests. This strategy not only streamlines the research process but also improves the reliability of results, making it a sensible, resource-efficient method that ultimately conserves public funding in the pursuit of AD treatments.
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Affiliation(s)
- Sudhir Kshirsagar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Md Ariful Islam
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Arubala P Reddy
- Nutritional Sciences Department, College of Human Sciences, Texas Tech University, Lubbock, TX, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
- Nutritional Sciences Department, College of Human Sciences, Texas Tech University, Lubbock, TX, USA
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, USA
- Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
- Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA
- Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA
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Kciuk M, Kruczkowska W, Gałęziewska J, Wanke K, Kałuzińska-Kołat Ż, Aleksandrowicz M, Kontek R. Alzheimer's Disease as Type 3 Diabetes: Understanding the Link and Implications. Int J Mol Sci 2024; 25:11955. [PMID: 39596023 PMCID: PMC11593477 DOI: 10.3390/ijms252211955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/04/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two prevalent conditions that present considerable public health issue in aging populations worldwide. Recent research has proposed a novel conceptualization of AD as "type 3 diabetes", highlighting the critical roles of insulin resistance and impaired glucose metabolism in the pathogenesis of the disease. This article examines the implications of this association, exploring potential new avenues for treatment and preventive strategies for AD. Key evidence linking diabetes to AD emphasizes critical metabolic processes that contribute to neurodegeneration, including inflammation, oxidative stress, and alterations in insulin signaling pathways. By framing AD within this metabolic context, we can enhance our understanding of its etiology, which in turn may influence early diagnosis, treatment plans, and preventive measures. Understanding AD as a manifestation of diabetes opens up the possibility of employing novel therapeutic strategies that incorporate lifestyle modifications and the use of antidiabetic medications to mitigate cognitive decline. This integrated approach has the potential to improve patient outcomes and deepen our comprehension of the intricate relationship between neurodegenerative diseases and metabolic disorders.
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Affiliation(s)
- Mateusz Kciuk
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland; (K.W.); (R.K.)
| | - Weronika Kruczkowska
- Department of Functional Genomics, Medical University of Lodz, 90-752 Lodz, Poland; (W.K.); (J.G.); (Ż.K.-K.)
| | - Julia Gałęziewska
- Department of Functional Genomics, Medical University of Lodz, 90-752 Lodz, Poland; (W.K.); (J.G.); (Ż.K.-K.)
| | - Katarzyna Wanke
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland; (K.W.); (R.K.)
| | - Żaneta Kałuzińska-Kołat
- Department of Functional Genomics, Medical University of Lodz, 90-752 Lodz, Poland; (W.K.); (J.G.); (Ż.K.-K.)
- Department of Biomedicine and Experimental Surgery, Medical University of Lodz, 90-136 Lodz, Poland
| | - Marta Aleksandrowicz
- Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland;
| | - Renata Kontek
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland; (K.W.); (R.K.)
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Liao W, Wei J, Liu C, Luo H, Ruan Y, Mai Y, Yu Q, Cao Z, Xu J, Zheng D, Sheng Z, Zhou X, Liu J. Magnesium-L-threonate treats Alzheimer's disease by modulating the microbiota-gut-brain axis. Neural Regen Res 2024; 19:2281-2289. [PMID: 38488562 PMCID: PMC11034594 DOI: 10.4103/1673-5374.391310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 10/07/2023] [Accepted: 11/06/2023] [Indexed: 04/24/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202410000-00029/figure1/v/2024-02-06T055622Z/r/image-tiff Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1). Here, we performed 16S rRNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-L-threonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesium-L-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins (zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.
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Affiliation(s)
- Wang Liao
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Jiana Wei
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
- Special Medical Service Center, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangdong, Guangdong Province, China
| | - Chongxu Liu
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Haoyu Luo
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Yuting Ruan
- Department of Rehabilitation, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Yingren Mai
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Qun Yu
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zhiyu Cao
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Jiaxin Xu
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Dong Zheng
- Department of Neurology, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Zonghai Sheng
- Institute of Biomedical and Health Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China
| | - Xianju Zhou
- Special Medical Service Center, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangdong, Guangdong Province, China
| | - Jun Liu
- Department of Neurology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China
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Jin S, Wang J, He Y. The brain network hub degeneration in Alzheimer's disease. BIOPHYSICS REPORTS 2024; 10:213-229. [PMID: 39281195 PMCID: PMC11399886 DOI: 10.52601/bpr.2024.230025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 04/26/2024] [Indexed: 09/18/2024] Open
Abstract
Alzheimer's disease (AD) has been conceptualized as a syndrome of brain network dysfunction. Recent imaging connectomics studies have provided unprecedented opportunities to map structural and functional brain networks in AD. By reviewing molecular, imaging, and computational modeling studies, we have shown that highly connected brain hubs are primarily distributed in the medial and lateral prefrontal, parietal, and temporal regions in healthy individuals and that the hubs are selectively and severely affected in AD as manifested by increased amyloid-beta deposition and regional atrophy, hypo-metabolism, and connectivity dysfunction. Furthermore, AD-related hub degeneration depends on the imaging modality with the most notable degeneration in the medial temporal hubs for morphological covariance networks, the prefrontal hubs for structural white matter networks, and in the medial parietal hubs for functional networks. Finally, the AD-related hub degeneration shows metabolic, molecular, and genetic correlates. Collectively, we conclude that the brain-network-hub-degeneration framework is promising to elucidate the biological mechanisms of network dysfunction in AD, which provides valuable information on potential diagnostic biomarkers and promising therapeutic targets for the disease.
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Affiliation(s)
- Suhui Jin
- Institute for Brain Research and Rehabilitation, Guangzhou 510631, China
| | - Jinhui Wang
- Institute for Brain Research and Rehabilitation, Guangzhou 510631, China
- Guangdong Key Laboratory of Mental Health and Cognitive Science, Guangzhou 510631, China
- Center for Studies of Psychological Application, South China Normal University, Guangzhou 510631, China
| | - Yong He
- IDG/McGovern Institute for Brain Research, Beijing 100875, China
- National Key Laboratory of Cognitive Neuroscience and Learning, Beijing 100875, China
- Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing 100875, China
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Vanderlip CR, Asch PA, Glavis-Bloom C. The Common Marmoset as a Translational Model for Longitudinal Studies of Cognitive Aging and Individual Vulnerability to Decline. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.22.609213. [PMID: 39229239 PMCID: PMC11370559 DOI: 10.1101/2024.08.22.609213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
In humans, cognitive aging is highly variable, with some individuals experiencing decline while others remain stable, and different cognitive domains exhibiting uneven vulnerability to aging. The neural mechanisms driving this intra- and inter-individual variability are not fully understood, making longitudinal studies in translational models essential for elucidating the timelines and processes involved. The common marmoset (Callithrix jacchus), a short-lived nonhuman primate, offers an unprecedented opportunity to conduct longitudinal investigations of aging and age-related disease over a condensed time frame, in a highly translatable animal model. The potential of the marmoset as a model for cognitive aging is indisputable, but a comprehensive cognitive battery tailored for longitudinal aging studies has not yet been developed, applied, or validated. This represents a critical missing piece for evaluating the marmoset as a model and understanding the extent to which marmoset cognitive aging mirrors the patterns found in humans, including whether marmosets have individual variability in their vulnerability to age-related cognitive decline. To address this, we developed a comprehensive touchscreen-based neuropsychological test battery for marmosets (MarmoCog), targeting five cognitive domains: working memory, stimulus-reward association learning, cognitive flexibility, motor speed, and motivation. We tested a large cohort of marmosets, ranging from young adults to geriatrics, over several years. We found significant variability in cognitive aging, with the greatest decline occurring in domains dependent on the prefrontal cortex and hippocampus. Additionally, we observed significant inter-individual variability in vulnerability to age-related cognitive decline: some marmosets declined across multiple domains, others in just one, and some showed no decline at all. This pattern mirrors human cognitive aging, solidifies the marmoset as an advantageous model for age-related cognitive decline, and provides a strong foundation for identifying the neural mechanisms involved.
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Affiliation(s)
- Casey R. Vanderlip
- Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA
| | - Payton A. Asch
- Systems Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Courtney Glavis-Bloom
- Systems Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
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Phulara NR, Rege A, Bieberich CJ, Seneviratne HK. Mass Spectrometry Imaging Reveals Region-Specific Lipid Alterations in the Mouse Brain in Response to Efavirenz Treatment. ACS Pharmacol Transl Sci 2024; 7:2379-2390. [PMID: 39156742 PMCID: PMC11326009 DOI: 10.1021/acsptsci.4c00228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/27/2024] [Accepted: 07/01/2024] [Indexed: 08/20/2024]
Abstract
Efavirenz (EFV) is a commonly used drug to treat human immunodeficiency virus infection and is known to exert adverse effects on the brain. Although it is known that EFV is associated with abnormal plasma lipid levels, the changes in the spatial localization of individual lipid molecules in brain tissue following EFV treatment are yet to be explored. In this study, we employed a matrix-assisted laser desorption/ionization mass spectrometry imaging approach to determine region-specific lipid alterations in mouse brains following EFV treatment. We detected unique spatial localization patterns of phosphatidylcholine (PC), sphingomyelin (SM), ceramide phosphoinositol (PI-Cer), and hexosylceramide (HexCer) molecules in the mouse brain. Interestingly, PC(32:0), PC(38:5), and SM(36:1;O2) showed high abundance in the hippocampus region, whereas PI-Cer(38:8) exhibited low abundance in the hippocampus region of the EFV-treated mouse brains. Additionally, we observed low abundance of PC(38:6), PC(40:6), and PI-Cer(40:3) in the thalamus region of the EFV-treated mouse brains. Furthermore, SM(40:1;O2), SM(42:2;O2), SM(42:1;O2), SM(43:2;O2), and SM(43:1;O2) exhibited their accumulation in the corpus callosum region of the EFV-treated mouse brains as compared to controls. However, HexCer(42:1;O3) exhibited depletion in the corpus callosum region in response to EFV treatment. To characterize the expression patterns of proteins, including lipid metabolizing enzymes, in response to EFV treatment, mass spectrometry-based proteomics was utilized. From these, the expression levels of 12 brain proteins were found to be significantly decreased following EFV treatment. Taken together, these multiomics data provide important insights into the effects of EFV on brain lipid metabolism.
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Affiliation(s)
- Nav Raj Phulara
- Department
of Chemistry and Biochemistry, University
of Maryland, Baltimore County, Baltimore, Maryland 21250, United States
| | - Apurv Rege
- Department
of Biological Sciences, University of Maryland,
Baltimore County, Baltimore, Maryland 21250, United States
| | - Charles J. Bieberich
- Department
of Biological Sciences, University of Maryland,
Baltimore County, Baltimore, Maryland 21250, United States
| | - Herana Kamal Seneviratne
- Department
of Chemistry and Biochemistry, University
of Maryland, Baltimore County, Baltimore, Maryland 21250, United States
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Odenkirk MT, Zheng X, Kyle JE, Stratton KG, Nicora CD, Bloodsworth KJ, Mclean CA, Masters CL, Monroe ME, Doecke JD, Smith RD, Burnum-Johnson KE, Roberts BR, Baker ES. Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer's Disease Across Distinct Brain Regions. J Proteome Res 2024; 23:2970-2985. [PMID: 38236019 PMCID: PMC11255128 DOI: 10.1021/acs.jproteome.3c00604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease with a complex etiology influenced by confounding factors such as genetic polymorphisms, age, sex, and race. Traditionally, AD research has not prioritized these influences, resulting in dramatically skewed cohorts such as three times the number of Apolipoprotein E (APOE) ε4-allele carriers in AD relative to healthy cohorts. Thus, the resulting molecular changes in AD have previously been complicated by the influence of apolipoprotein E disparities. To explore how apolipoprotein E polymorphism influences AD progression, 62 post-mortem patients consisting of 33 AD and 29 controls (Ctrl) were studied to balance the number of ε4-allele carriers and facilitate a molecular comparison of the apolipoprotein E genotype. Lipid and protein perturbations were assessed across AD diagnosed brains compared to Ctrl brains, ε4 allele carriers (APOE4+ for those carrying 1 or 2 ε4s and APOE4- for non-ε4 carriers), and differences in ε3ε3 and ε3ε4 Ctrl brains across two brain regions (frontal cortex (FCX) and cerebellum (CBM)). The region-specific influences of apolipoprotein E on AD mechanisms showcased mitochondrial dysfunction and cell proteostasis at the core of AD pathophysiology in the post-mortem brains, indicating these two processes may be influenced by genotypic differences and brain morphology.
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Affiliation(s)
- Melanie T Odenkirk
- Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27606, United States of America
| | - Xueyun Zheng
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United States of America
| | - Jennifer E Kyle
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United States of America
| | - Kelly G Stratton
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United States of America
| | - Carrie D Nicora
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United States of America
| | - Kent J Bloodsworth
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United States of America
| | - Catriona A Mclean
- Anatomical Pathology, Alfred Hospital, Prahran, Victoria 3181, Australia
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Colin L Masters
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Matthew E Monroe
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United States of America
| | - James D Doecke
- CSIRO Health and Biosecurity, Herston, Queensland 4029, Australia
| | - Richard D Smith
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99354, United States of America
| | - Kristin E Burnum-Johnson
- Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99354, United States of America
| | - Blaine R Roberts
- Department of Biochemistry, Emory University, Atlanta, Georgia 30322, United States of America
- Department of Neurology, Emory University, Atlanta, Georgia 30322, United States of America
| | - Erin S Baker
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, United States of America
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11
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Vanderlip CR, Jutras ML, Asch PA, Zhu SY, Lerma MN, Buffalo EA, Glavis-Bloom C. Parallel patterns of cognitive aging in marmosets and macaques. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.22.604411. [PMID: 39091859 PMCID: PMC11291085 DOI: 10.1101/2024.07.22.604411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
As humans age, some experience cognitive impairment while others do not. When impairment does occur, it is not expressed uniformly across cognitive domains and varies in severity across individuals. Translationally relevant model systems are critical for understanding the neurobiological drivers of this variability, which is essential to uncovering the mechanisms underlying the brain's susceptibility to the effects of aging. As such, non-human primates are particularly important due to shared behavioral, neuroanatomical, and age-related neuropathological features with humans. For many decades, macaque monkeys have served as the primary non-human primate model for studying the neurobiology of cognitive aging. More recently, the common marmoset has emerged as an advantageous model for this work due to its short lifespan that facilitates longitudinal studies. Despite their growing popularity as a model, whether marmosets exhibit patterns of age-related cognitive impairment comparable to those observed in macaques and humans remains unexplored. To address this major limitation for the development and evaluation of the marmoset as a model of cognitive aging, we directly compared working memory ability as a function of age in macaques and marmosets on the identical working memory task. Our results demonstrate that marmosets and macaques exhibit remarkably similar age-related working memory deficits, highlighting the value of the marmoset as a model for cognitive aging research within the neuroscience community.
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Affiliation(s)
- Casey R. Vanderlip
- Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA
| | - Megan L. Jutras
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA, USA
- Washington National Primate Research Center, Seattle, WA, USA
| | - Payton A. Asch
- Systems Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Stephanie Y. Zhu
- Department of Biology, University of Washington, Seattle, WA, USA
| | - Monica N. Lerma
- Washington National Primate Research Center, Seattle, WA, USA
- Department of Brain Science, Allen Institute for Brain Science, Seattle, WA, USA
| | - Elizabeth A. Buffalo
- Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA, USA
- Washington National Primate Research Center, Seattle, WA, USA
| | - Courtney Glavis-Bloom
- Systems Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
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12
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Bou Ghanem A, Hussayni Y, Kadbey R, Ratel Y, Yehya S, Khouzami L, Ghadieh HE, Kanaan A, Azar S, Harb F. Exploring the complexities of 1C metabolism: implications in aging and neurodegenerative diseases. Front Aging Neurosci 2024; 15:1322419. [PMID: 38239489 PMCID: PMC10794399 DOI: 10.3389/fnagi.2023.1322419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/11/2023] [Indexed: 01/22/2024] Open
Abstract
The intricate interplay of one-carbon metabolism (OCM) with various cellular processes has garnered substantial attention due to its fundamental implications in several biological processes. OCM serves as a pivotal hub for methyl group donation in vital biochemical reactions, influencing DNA methylation, protein synthesis, and redox balance. In the context of aging, OCM dysregulation can contribute to epigenetic modifications and aberrant redox states, accentuating cellular senescence and age-associated pathologies. Furthermore, OCM's intricate involvement in cancer progression is evident through its capacity to provide essential one-carbon units crucial for nucleotide synthesis and DNA methylation, thereby fueling uncontrolled cell proliferation and tumor development. In neurodegenerative disorders like Alzheimer's and Parkinson's, perturbations in OCM pathways are implicated in the dysregulation of neurotransmitter synthesis and mitochondrial dysfunction, contributing to disease pathophysiology. This review underscores the profound impact of OCM in diverse disease contexts, reinforcing the need for a comprehensive understanding of its molecular complexities to pave the way for targeted therapeutic interventions across inflammation, aging and neurodegenerative disorders.
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Affiliation(s)
- Ayman Bou Ghanem
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Yaman Hussayni
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Raghid Kadbey
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Yara Ratel
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Shereen Yehya
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Lara Khouzami
- College of Natural and Health Sciences, Zayed University, Dubai, United Arab Emirates
| | - Hilda E. Ghadieh
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
- AUB Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
| | - Amjad Kanaan
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Sami Azar
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
| | - Frederic Harb
- Faculty of Medicine and Medical Sciences, University of Balamand, Tripoli, Lebanon
- AUB Diabetes, American University of Beirut Medical Center, Beirut, Lebanon
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13
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Foster SG, Mathew S, Labarre A, Parker JA, Tompkins TA, Binda S. Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179 Prolong Lifespan and Mitigate Amyloid-β Toxicity in C. elegans via Distinct Mechanisms. J Alzheimers Dis 2024; 101:49-60. [PMID: 39093068 PMCID: PMC11380293 DOI: 10.3233/jad-230948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Background Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer's disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. Objective We sought to identify probiotics that can delay Aβ-induced paralysis. Methods Using C. elegans expressing human amyloid-β (Aβ)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. Results We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-β aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Conclusions Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.
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Affiliation(s)
- Stuart G Foster
- Rosell Institute for Microbiome and Probiotics, Montreal, QC, Canada
| | - Shibi Mathew
- Rosell Institute for Microbiome and Probiotics, Montreal, QC, Canada
| | - Audrey Labarre
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Department of Neuroscience, University of Montreal, Montreal, QC, Canada
| | - J Alex Parker
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Department of Neuroscience, University of Montreal, Montreal, QC, Canada
| | - Thomas A Tompkins
- Rosell Institute for Microbiome and Probiotics, Montreal, QC, Canada
| | - Sylvie Binda
- Rosell Institute for Microbiome and Probiotics, Montreal, QC, Canada
- Lallemand Health Solutions Inc., Blagnac Cedex, France
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14
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Xu H, Luo Z, Zhang R, Golovynska I, Huang Y, Samanta S, Zhou T, Li S, Guo B, Liu L, Weng X, He J, Liao C, Wang Y, Ohulchanskyy TY, Qu J. Exploring the effect of photobiomodulation and gamma visual stimulation induced by 808 nm and visible LED in Alzheimer's disease mouse model. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2024; 250:112816. [PMID: 38029664 DOI: 10.1016/j.jphotobiol.2023.112816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 11/08/2023] [Accepted: 11/20/2023] [Indexed: 12/01/2023]
Abstract
Although photobiomodulation (PBM) and gamma visual stimulatqion (GVS) have been overwhelmingly explored in the recent time as a possible light stimulation (LS) means of Alzheimer's disease (AD) therapy, their effects have not been assessed at once. In our research, the AD mouse model was stimulated using light with various parameters [continuous wave (PBM) or 40 Hz pulsed visible LED (GVS) or 40 Hz pulsed 808 nm LED (PBM and GVS treatment)]]. The brain slices collected from the LS treated AD model mice were evaluated using (i) fluorescence microscopy to image thioflavine-S labeled amy-loid-β (Aβ) plaques (the main hallmark of AD), or (ii) two-photon excited fluorescence (TPEF) imaging of unlabeled Aβ plaques, showing that the amount of Aβ plaques was reduced after LS treatment. The imaging results correlated well with the results of Morris water maze (MWM) test, which demonstrated that the spatial learning and memory abilities of LS treated mice were noticeably higher than those of untreated mice. The LS effect was also assessed by in vivo nonlinear optical imaging, revealing that the cerebral amyloid angiopathy decreased spe-cifically as a result of 40 Hz pulsed 808 nm irradiation, on the contrary, the angiopathy reversed after visible 40 Hz pulsed light treatment. The obtained results provide useful reference for further optimization of the LS (PBM or GVS) parameters to achieve efficient phototherapy of AD.
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Affiliation(s)
- Hao Xu
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Ziyi Luo
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Renlong Zhang
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Iuliia Golovynska
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Yanxia Huang
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Soham Samanta
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Ting Zhou
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Shaowei Li
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Bingang Guo
- HOLOKOOK Co. LtD, Shenzhen 518060, Guangdong Province, P.R. China
| | - Liwei Liu
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Xiaoyu Weng
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Jun He
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Changrui Liao
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Yiping Wang
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China
| | - Tymish Y Ohulchanskyy
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China.
| | - Junle Qu
- Key Laboratory of Optoelectronics Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R. China; Engineering Research Center of Optical Instrument and System, Ministry of Education, Shanghai Key Lab of Modern Optical System, School of Optical-Electrical and Computer Engineering, University of Shanghai for Science and Technology, Shanghai 200093, P.R. China.
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15
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Kashtanova DA, Mamchur AA, Dzhumaniyazova IH, Ivanov MV, Erema VV, Zelenova EA, Yakovchik AY, Gusakova MS, Rumyantseva AM, Terekhov MV, Matkava LR, Akopyan AA, Strazhesko ID, Yudin VS, Makarov VV, Kraevoy SA, Tkacheva ON, Yudin SM. Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein. Front Aging Neurosci 2023; 15:1273825. [PMID: 37953886 PMCID: PMC10637623 DOI: 10.3389/fnagi.2023.1273825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/11/2023] [Indexed: 11/14/2023] Open
Abstract
Background Cognitive impairment is an irreversible, aging-associated condition that robs people of their independence. The purpose of this study was to investigate possible causes of this condition and propose preventive options. Methods We assessed cognitive status in long-living adults aged 90+ (n = 2,559) and performed a genome wide association study using two sets of variables: Mini-Mental State Examination scores as a continuous variable (linear regression) and cognitive status as a binary variable (> 24, no cognitive impairment; <10, impairment) (logistic regression). Results Both variations yielded the same polymorphisms, including a well-known marker of dementia, rs429358in the APOE gene. Molecular dynamics simulations showed that this polymorphism leads to changes in the structure of alpha helices and the mobility of the lipid-binding domain in the APOE protein. Conclusion These changes, along with higher LDL and total cholesterol levels, could be the mechanism underlying the development of cognitive impairment in older adults. However, this polymorphism is not the only determining factor in cognitive impairment. The polygenic risk score model included 45 polymorphisms (ROC AUC 69%), further confirming the multifactorial nature of this condition. Our findings, particularly the results of PRS modeling, could contribute to the development of early detection strategies for predisposition to cognitive impairment in older adults.
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Affiliation(s)
- D. A. Kashtanova
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - A. A. Mamchur
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - I. H. Dzhumaniyazova
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - M. V. Ivanov
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - V. V. Erema
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - E. A. Zelenova
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - A. Y. Yakovchik
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - M. S. Gusakova
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - A. M. Rumyantseva
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - M. V. Terekhov
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - L. R. Matkava
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - A. A. Akopyan
- Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - I. D. Strazhesko
- Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - V. S. Yudin
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - V. V. Makarov
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - S. A. Kraevoy
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
| | - O. N. Tkacheva
- Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - S. M. Yudin
- Federal State Budgetary Institution “Centre for Strategic Planning and Management of Biomedical Health Risks”, Federal Medical Biological Agency, Moscow, Russia
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16
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Yu W, Chen L, Li X, Han T, Yang Y, Hu C, Yu W, Lü Y. Alteration of Metabolic Profiles during the Progression of Alzheimer's Disease. Brain Sci 2023; 13:1459. [PMID: 37891827 PMCID: PMC10605479 DOI: 10.3390/brainsci13101459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/25/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
(1) Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that threatens the population health of older adults. However, the mechanisms of the altered metabolism involved in AD pathology are poorly understood. The aim of the study was to identify the potential biomarkers of AD and discover the metabolomic changes produced during the progression of the disease. (2) Methods: Gas chromatography-mass spectrometry (GC-MS) was used to measure the concentrations of the serum metabolites in a cohort of subjects with AD (n = 88) and a cognitively normal control (CN) group (n = 85). The patients were classified as very mild (n = 25), mild (n = 27), moderate (n = 25), and severe (n = 11). The serum metabolic profiles were analyzed using multivariate and univariate approaches. Least absolute shrinkage and selection operator (LASSO) logistic regression was applied to identify the potential biomarkers of AD. Biofunctional enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes. (3) Results: Our results revealed considerable separation between the AD and CN groups. Six metabolites were identified as potential biomarkers of AD (AUC > 0.85), and the diagnostic model of three metabolites could predict the risk of AD with high accuracy (AUC = 0.984). The metabolic enrichment analysis revealed that carbohydrate metabolism deficiency and the disturbance of amino acid, fatty acid, and lipid metabolism were involved in AD progression. Especially, the pathway analysis highlighted that l-glutamate participated in four crucial nervous system pathways (including the GABAergic synapse, the glutamatergic synapse, retrograde endocannabinoid signaling, and the synaptic vesicle cycle). (4) Conclusions: Carbohydrate metabolism deficiency and amino acid dysregulation, fatty acid, and lipid metabolism disorders were pivotal events in AD progression. Our study may provide novel insights into the role of metabolic disorders in AD pathogenesis and identify new markers for AD diagnosis.
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Affiliation(s)
- Wuhan Yu
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; (W.Y.); (L.C.)
| | - Lihua Chen
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; (W.Y.); (L.C.)
| | - Xuebing Li
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; (W.Y.); (L.C.)
| | - Tingli Han
- Department of Obsetric and Gyncology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Liggins Institute, The University of Auckland, Auckland 1023, New Zealand
| | - Yang Yang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400716, China
| | - Cheng Hu
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; (W.Y.); (L.C.)
| | - Weihua Yu
- Institutes of Neuroscience, Chongqing Medical University, Chongqing 400016, China
| | - Yang Lü
- Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; (W.Y.); (L.C.)
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17
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Samuelsson J, Marseglia A, Lindberg O, Westman E, Pereira JB, Shams S, Kern S, Ahlner F, Rothenberg E, Skoog I, Zettergren A. Associations between dietary patterns and dementia-related neuroimaging markers. Alzheimers Dement 2023; 19:4629-4640. [PMID: 36960849 DOI: 10.1002/alz.13048] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/03/2023] [Accepted: 02/21/2023] [Indexed: 03/25/2023]
Abstract
BACKGROUND The exploration of associations between dietary patterns and dementia-related neuroimaging markers can provide insights on food combinations that may impact brain integrity. METHODS Data were derived from the Swedish Gothenburg H70 Birth Cohort Study (n = 610). Three dietary patterns were obtained using principal component analysis. Magnetic resonance imaging markers included cortical thickness, an Alzheimer's disease (AD) signature score, small vessel disease, and white matter microstructural integrity. Adjusted linear/ordinal regression analyses were performed. RESULTS A high-protein and alcohol dietary pattern was negatively associated with cortical thickness in the whole brain (Beta: -0.011; 95% confidence interval [CI]: -0.018 to -0.003), and with an Alzheimer's disease cortical thickness signature score (Beta: -0.013; 95% CI: -0.024 to -0.001). A positive association was found between a Mediterranean-like dietary pattern and white matter microstructural integrity (Beta: 0.078; 95% CI: 0.002-0.154). No associations were found with a Western-like dietary pattern. DISCUSSION Dietary patterns may impact brain integrity through neurodegenerative and vascular pathways. HIGHLIGHTS Certain dietary patterns were associated with dementia-related neuroimaging markers. A Mediterranean dietary pattern was positively associated with white matter microstructure. A high-protein and alcohol pattern was negatively associated with cortical thickness.
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Affiliation(s)
- Jessica Samuelsson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Neuropsychiatric Epidemiology Unit, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP), University of Gothenburg, Mölndal, Sweden
| | - Anna Marseglia
- Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
| | - Olof Lindberg
- Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
| | - Eric Westman
- Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
| | - Joana B Pereira
- Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmo, Sweden
| | - Sara Shams
- Department of Radiology, Karolinska University Hospital, The Institution for Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Radiology, Stanford University Hospital, Stanford, California, USA
| | - Silke Kern
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Neuropsychiatric Epidemiology Unit, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP), University of Gothenburg, Mölndal, Sweden
| | - Felicia Ahlner
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Neuropsychiatric Epidemiology Unit, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP), University of Gothenburg, Mölndal, Sweden
| | | | - Ingmar Skoog
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Neuropsychiatric Epidemiology Unit, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP), University of Gothenburg, Mölndal, Sweden
- Department of Psychiatry, Cognition and Old Age Psychiatry, Sahlgrenska University Hospital, Region Västra Götaland, Mölndal, Sweden
| | - Anna Zettergren
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Neuropsychiatric Epidemiology Unit, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP), University of Gothenburg, Mölndal, Sweden
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18
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Zambrano P, Jemiola-Rzeminska M, Muñoz-Torrero D, Suwalsky M, Strzalka K. A rhein-huprine hybrid protects erythrocyte membrane integrity against Alzheimer's disease related Aβ(1-42) peptide. Biophys Chem 2023; 300:107061. [PMID: 37307659 DOI: 10.1016/j.bpc.2023.107061] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 05/26/2023] [Accepted: 06/02/2023] [Indexed: 06/14/2023]
Abstract
Alzheimer's disease remains largely unknown, and currently there is no complete cure for the disease. New synthetic approaches have been developed to create multi-target agents, such as RHE-HUP, a rhein-huprine hybrid which can modulate several biological targets that are relevant to the development of the disease. While RHE-HUP has shown in vitro and in vivo beneficial effects, the molecular mechanisms by which it exerts its protective effect on cell membranes have not been fully clarified. To better understand RHE-HUP interactions with cell membranes, we used synthetic membrane models and natural models of human membranes. For this purpose, human erythrocytes and molecular model of its membrane built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. The latter correspond to classes of phospholipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively. X-ray diffraction and differential scanning calorimetry (DSC) results indicated that RHE-HUP was able to interact mainly with DMPC. In addition, scanning electron microscopy (SEM) analysis showed that RHE-HUP modified the normal biconcave shape of erythrocytes inducing the formation of echinocytes. Moreover, the protective effect of RHE-HUP against the disruptive effect of Aβ(1-42) on the studied membrane models was tested. X-ray diffraction experiments showed that RHE-HUP induced a recovery in the ordering of DMPC multilayers after the disruptive effect of Aβ(1-42), confirming the protective role of the hybrid.
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Affiliation(s)
- Pablo Zambrano
- Facultad de Ciencias Químicas, Universidad de Concepción, Concepción, Chile.
| | - Malgorzata Jemiola-Rzeminska
- Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Diego Muñoz-Torrero
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
| | - Mario Suwalsky
- Facultad de Medicina, Universidad Católica de la Santísima Concepción, Concepción, Chile
| | - Kazimierz Strzalka
- Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
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Wu X, Guo J, Chen X, Han P, Huang L, Peng Y, Zhou X, Huang J, Wei C, Zheng Y, Zhang Z, Li M, Guo Q. Comparison of the relationship between cognitive function and future falls in Chinese community-dwelling older adults with and without diabetes mellitus. J Formos Med Assoc 2023; 122:603-611. [PMID: 36336606 DOI: 10.1016/j.jfma.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE The aim of this study was to determine whether cognitive function is associated with future falls in older patients with diabetes mellitus (DM) compared with those without DM. Cognitive function was divided into several domains to further analyze. METHODS A total of 678 individuals met the inclusion criteria and comprised the final study population. The mean age was 74.35 ± 5.35 years, and 58.9% of the participants were female (n = 400). At the baseline, cognitive function was measured by the Mini Mental State Examination (MMSE), and DM diagnoses were determined by medical records. The self-reported any falls data were obtained via face-to-face questioning at the 1-year follow-up. RESULTS At baseline, 15.6% of participants (n = 106) were diagnosed with DM. According to whether they had any falls during 1-year follow-up, there was a significant difference between the two group in fasting plasma glucose (p = 0.012) and DM (p = 0.036) at baseline. Among the older adults with DM, those who had experienced any falls had poorer cognitive function (p = 0.014). After adjusting for various covariates, we found that MMSE (95% CI 0.790-0.991, p = 0.034), orientation to place (95% CI 0.307-0.911, p = 0.022) and registration (95% CI 0.162-0.768, p = 0.009) were significantly associated with falls in the follow-up. CONCLUSION Our study found that in patients with DM, cognitive function is related to future falls. Not only overall cognitive function, but also orientation to place and registration were all associated with future falls in older adults with DM. When completing the fall risk assessment of elderly patients with DM, clinicians should give more attention to the testing of cognitive function.
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Affiliation(s)
- Xinze Wu
- Department of Rehabilitation Medicine, Tianjin Medical University, Tianjin, China; Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine, Tohoku University, Sendai, Japan; Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Pudong New District, Shanghai, China
| | - Jinlong Guo
- Department of Rehabilitation Medicine, Tianjin Medical University, Tianjin, China
| | - Xinlong Chen
- Department of Rehabilitation Medicine, Tianjin Medical University, Tianjin, China
| | - Peipei Han
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Pudong New District, Shanghai, China
| | - Liqin Huang
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Pudong New District, Shanghai, China
| | - Youran Peng
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Pudong New District, Shanghai, China
| | - Xin Zhou
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Pudong New District, Shanghai, China
| | - Jiasen Huang
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Pudong New District, Shanghai, China
| | - Chengyao Wei
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Pudong New District, Shanghai, China
| | | | | | - Ming Li
- Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Pudong New District, Shanghai, China
| | - Qi Guo
- Department of Rehabilitation Medicine, Tianjin Medical University, Tianjin, China; Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Pudong New District, Shanghai, China.
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Dhingra A, Tobias JW, Philp NJ, Boesze-Battaglia K. Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice. Int J Mol Sci 2023; 24:6716. [PMID: 37047689 PMCID: PMC10095460 DOI: 10.3390/ijms24076716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/28/2023] [Accepted: 03/28/2023] [Indexed: 04/14/2023] Open
Abstract
LC3b (Map1lc3b) plays an essential role in canonical autophagy and is one of several components of the autophagy machinery that mediates non-canonical autophagic functions. Phagosomes are often associated with lipidated LC3b to promote phagosome maturation in a process called LC3-associated phagocytosis (LAP). Specialized phagocytes, such as mammary epithelial cells, retinal pigment epithelial (RPE) cells, and sertoli cells, utilize LAP for optimal degradation of phagocytosed material, including debris. In the visual system, LAP is critical to maintain retinal function, lipid homeostasis, and neuroprotection. In a mouse model of retinal lipid steatosis-mice lacking LC3b (LC3b-/-), we observed increased lipid deposition, metabolic dysregulation, and enhanced inflammation. Herein, we present a non-biased approach to determine if loss of LAP mediated processes modulate the expression of various genes related to metabolic homeostasis, lipid handling, and inflammation. A comparison of the RPE transcriptome of WT and LC3b-/- mice revealed 1533 DEGs, with ~73% upregulated and 27% downregulated. Enriched gene ontology (GO) terms included inflammatory response (upregulated DEGs), fatty acid metabolism, and vascular transport (downregulated DEGs). Gene set enrichment analysis (GSEA) identified 34 pathways; 28 were upregulated (dominated by inflammation/related pathways) and 6 were downregulated (dominated by metabolic pathways). Analysis of additional gene families identified significant differences for genes in the solute carrier family, RPE signature genes, and genes with a potential role in age-related macular degeneration. These data indicate that loss of LC3b induces robust changes in the RPE transcriptome contributing to lipid dysregulation and metabolic imbalance, RPE atrophy, inflammation, and disease pathophysiology.
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Affiliation(s)
- Anuradha Dhingra
- Department of Basic and Translational Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - John W. Tobias
- Penn Genomics and Sequencing Core, Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nancy J. Philp
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Kathleen Boesze-Battaglia
- Department of Basic and Translational Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
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Dhingra A, Tobias JW, Philp NJ, Boesze-Battaglia K. Transcriptomic changes predict metabolic alterations in LC3 associated phagocytosis in aged mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.14.532586. [PMID: 36993501 PMCID: PMC10054970 DOI: 10.1101/2023.03.14.532586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
LC3b ( Map1lc3b ) plays an essential role in canonical autophagy and is one of several components of the autophagy machinery that mediates non-canonical autophagic functions. Phagosomes are often associated with lipidated LC3b, to pro-mote phagosome maturation in a process called LC3-associated phagocytosis (LAP). Specialized phagocytes such as mammary epithelial cells, retinal pigment epithelial (RPE) cells, and sertoli cells utilize LAP for optimal degradation of phagocytosed material, including debris. In the visual system, LAP is critical to maintain retinal function, lipid homeostasis and neuroprotection. In a mouse model of retinal lipid steatosis - mice lacking LC3b ( LC3b -/- ), we observed increased lipid deposition, metabolic dysregulation and enhanced inflammation. Herein we present a non-biased approach to determine if loss of LAP mediated processes modulate the expression of various genes related to metabolic homeostasis, lipid handling, and inflammation. A comparison of the RPE transcriptome of WT and LC3b -/- mice revealed 1533 DEGs, with ~73% upregulated and 27% down-regulated. Enriched gene ontology (GO) terms included inflammatory response (upregulated DEGs), fatty acid metabolism and vascular transport (downregulated DEGs). Gene set enrichment analysis (GSEA) identified 34 pathways; 28 were upregulated (dominated by inflammation/related pathways) and 6 were downregulated (dominated by metabolic pathways). Analysis of additional gene families identified significant differences for genes in the solute carrier family, RPE signature genes, and genes with potential role in age-related macular degeneration. These data indicate that loss of LC3b induces robust changes in the RPE transcriptome contributing to lipid dysregulation and metabolic imbalance, RPE atrophy, inflammation, and disease pathophysiology.
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Li K, Chi R, Liu L, Feng M, Su K, Li X, He G, Shi Y. 3D genome-selected microRNAs to improve Alzheimer's disease prediction. Front Neurol 2023; 14:1059492. [PMID: 36860572 PMCID: PMC9968804 DOI: 10.3389/fneur.2023.1059492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 01/16/2023] [Indexed: 02/15/2023] Open
Abstract
Introduction Alzheimer's disease (AD) is a type of neurodegenerative disease that has no effective treatment in its late stage, making the early prediction of AD critical. There have been an increase in the number of studies indicating that miRNAs play an important role in neurodegenerative diseases including Alzheimer's disease via epigenetic modifications including DNA methylation. Therefore, miRNAs may serve as excellent biomarkers in early AD prediction. Methods Considering that the non-coding RNAs' activity may be linked to their corresponding DNA loci in the 3D genome, we collected the existing AD-related miRNAs combined with 3D genomic data in this study. We investigated three machine learning models in this work under leave-one-out cross-validation (LOOCV): support vector classification (SVC), support vector regression (SVR), and knearest neighbors (KNNs). Results The prediction results of different models demonstrated the effectiveness of incorporating 3D genome information into the AD prediction models. Discussion With the assistance of the 3D genome, we were able to train more accurate models by selecting fewer but more discriminatory miRNAs, as witnessed by several ML models. These interesting findings indicate that the 3D genome has great potential to play an important role in future AD research.
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Affiliation(s)
- Keyi Li
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China,Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
| | - Runqiu Chi
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China,Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
| | - Liangjie Liu
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China,Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
| | - Mofan Feng
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China,Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
| | - Kai Su
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China,Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China
| | - Xia Li
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang He
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China,Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China,*Correspondence: Guang He ✉
| | - Yi Shi
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China,Shanghai Key Laboratory of Psychotic Disorders, Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China,Yi Shi ✉
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Yang L, Nao J. Focus on Alzheimer's Disease: The Role of Fibroblast Growth Factor 21 and Autophagy. Neuroscience 2023; 511:13-28. [PMID: 36372296 DOI: 10.1016/j.neuroscience.2022.11.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/24/2022] [Accepted: 11/04/2022] [Indexed: 11/13/2022]
Abstract
Alzheimer's disease (AD) is a disorder of the central nervous system that is typically marked by progressive cognitive impairment and memory loss. Amyloid β plaque deposition and neurofibrillary tangles with hyperphosphorylated tau are the two hallmark pathologies of AD. In mammalian cells, autophagy clears aberrant protein aggregates, thus maintaining proteostasis as well as neuronal health. Autophagy affects production and metabolism of amyloid β and accumulation of phosphorylated tau proteins, whose malfunction can lead to the progression of AD. On the other hand, defective autophagy has been found to induce the production of the neuroprotective factor fibroblast growth factor 21 (FGF21), although the underlying mechanism is unclear. In this review, we highlight the significance of aberrant autophagy in the pathogenesis of AD, discuss the possible mechanisms by which defective autophagy induces FGF21 production, and analyze the potential of FGF21 in the treatment of AD. The findings provide some insights into the potential role of FGF21 and autophagy in the pathogenesis of AD.
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Affiliation(s)
- Lan Yang
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Jianfei Nao
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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Ali DG, Abner EL, Bahrani AA, El Khouli R, Gold BT, Jiang Y, Wilcock DM, Jicha GA. Amyloid-PET and White Matter Hyperintensities Have Independent Effects on Baseline Cognitive Function and Synergistic Effects on Longitudinal Executive Function. Brain Sci 2023; 13:218. [PMID: 36831761 PMCID: PMC9953773 DOI: 10.3390/brainsci13020218] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 01/31/2023] Open
Abstract
Co-occurrence of beta amyloid (Aβ) and white matter hyperintensities (WMHs) increase the risk of dementia and both are considered biomarkers of preclinical dementia. Moderation and mediation modeling were used to define the interplay between global and regional Aβ and WMHs measures in relation to executive function (EF) and memory composite scores outcomes at baseline and after approximately 2 years across a sample of 714 clinically normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI 2). The moderation regression analysis showed additive effects of Aβ and WMHs over baseline memory and EF scores (p = 0.401 and 0.061, respectively) and synergistic effects over follow-up EF (p < 0.05). Through mediation analysis, the data presented demonstrate that WMHs effects, mediated by global and regional amyloid burden, are responsible for baseline cognitive performance deficits in memory and EF. These findings suggest that Aβ and WMHs contribute to baseline cognition independently while WMHs volumes exert effects on baseline cognitive performance directly and through influences on Aβ accumulation.
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Affiliation(s)
- Doaa G. Ali
- Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
- Department of Behavioral Science, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
| | - Erin L. Abner
- Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
- Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, KY 40536, USA
| | - Ahmed A. Bahrani
- Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
- Department of Neurology, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
| | - Riham El Khouli
- Department of Radiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Brian T. Gold
- Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
- Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Yang Jiang
- Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
- Department of Behavioral Science, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
| | - Donna M. Wilcock
- Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
| | - Gregory A. Jicha
- Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
- Department of Behavioral Science, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
- Department of Neurology, College of Medicine, University of Kentucky, Lexington, KY 40506, USA
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Nabizadeh F, Kankam SB, Balabandian M, Hashemi SM, Sharifkazemi H, Rostami MR. Metformin use and brain atrophy in nondemented elderly individuals with diabetes. Exp Gerontol 2022; 166:111890. [PMID: 35843348 DOI: 10.1016/j.exger.2022.111890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/28/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022]
Abstract
OBJECTIVE There is a shred of growing evidence demonstrating that diabetic patients are at higher risk of developing Alzheimer's disease compared to the general population. The previous investigation showed the protective effect of metformin for delaying dementia in diabetic patients. However, there are limited data on the effect of metformin on structural changes. This study aims to investigate the effect of metformin on hippocampal and cortical volumes in non-demented diabetic individuals. METHOD We entered 157 non-demented diabetic subjects including 89 mild cognitive impairment (MCI), and 68 cognitively healthy individuals from Alzheimer's disease Neuroimaging Initiative (ADNI) which were then categorized as metformin users and non-users. We used the ANCOVA model for measuring the association between metformin use and hippocampal and cortical volumes. RESULTS Among 157 subjects with a mean age of 71.8 (±7.7) included in this study, 76 individuals were stratified as metformin users. Results of the univariate model indicate that metformin users had a higher right (p = 0.003) and left parietal lobe volume (p = 0.004). Moreover, the volume of left cingulate was higher in those who used metformin compared to those not used it (p = 0.027). Our results were also significant for the right frontal lobe and indicated that metformin users had higher volume (p = 0.035). There were no significant differences in the hippocampus, occipital, and temporal regions. CONCLUSION Our findings showed the protective effects of metformin on brain volumes in non-demented elderly individuals with diabetes. Comparing the groups show strong enough results regarding the lower atrophy in metformin users.
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Affiliation(s)
- Fardin Nabizadeh
- Neuroscience Research Group (NRG), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | | | - Mohammad Balabandian
- Neuroscience Research Group (NRG), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | | | - Mohammad Reza Rostami
- Neuroscience Research Group (NRG), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Sharma K, Basu-Ray I, Sayal N, Vora A, Bammidi S, Tyagi R, Modgil S, Bali P, Kaur P, Goyal AK, Pal DK, Arvind H, Jindal K, Garg V, Matyal B, Thakur N, Chhikara A, Kaur N, Maanju P, Bhatia KS, Pannu V, Gupta V, Malik N, Malik R, Kumar R, Kaur R, Bhatt V, Bhalla A, Mohanty M, Singh G, Sharma SK, Sivapuram MS, Mathur D, Khanra D, Anand A. Yoga as a Preventive Intervention for Cardiovascular Diseases and Associated Comorbidities: Open-Label Single Arm Study. Front Public Health 2022; 10:843134. [PMID: 35769774 PMCID: PMC9234218 DOI: 10.3389/fpubh.2022.843134] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 04/27/2022] [Indexed: 11/20/2022] Open
Abstract
Aim Common Yoga Protocol (CYP) is a standardized yoga protocol authored by experts from all over the world under the aegis of the Ministry of AYUSH, Ayurveda, Yoga and Naturopathy, Unani, Siddha, Sowa Rigpa and Homeopathy (AYUSH). The potential of CYP can be determined as a cost-effective lifestyle modification to prevent the risk of developing cardiovascular diseases (CVD). Methods In this prospective trial, we compared the effect of CYP at baseline and after 1 month. A total of 374 yoga-naïve participants performed CYP under the supervision of experienced trainers. Physiological [body mass index (BMI), blood pressure, percent oxygen saturation], biochemical (fasting blood glucose and lipid profile), and neurocognitive parameters were measured before and after the intervention. Results At day 30 of yoga practice, serum levels of low-density lipoprotein (LDL), total cholesterol (TC), and high-density lipoprotein (HDL) were found significantly improved as compared to the baseline levels observed at the time of enrollment. Similarly, the lipid profile was also obtained from experienced trainers and found to be significantly different from those of yoga-naïve volunteers. When the intervention was compared between the healthy yoga-naïve participants with yoga-naïve participants suffering from medical issues, it was found that cholesterol profile improved significantly in the healthy-naive group as compared to the diseased group (hypertension, diabetes, underwent surgery, and CVD). Conclusion These results highlight the need for further research to better understand the effects of yoga on the primary prevention of CVD.
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Affiliation(s)
- Kaushal Sharma
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
- Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh, India
| | - Indranill Basu-Ray
- Department of Cardiology, St. Francis Hospital, Memphis, TN, United States
- Department of Cardiology, All India Institute of Medical Sciences, Virbhadra Marg, Rishikesh, India
- Department of Cardiology, Swami Vivekananda Yoga Anusandhana Samsthana, Union Territory (SVYASA), Bengaluru, India
| | - Natasha Sayal
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ariana Vora
- Department of Physical Medicine and Rehabilitation, Massachusetts General Hospital, Boston, MA, United States
| | - Sridhar Bammidi
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Rahul Tyagi
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Shweta Modgil
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
- Department of Zoology, Panjab University, Chandigarh, India
| | - Parul Bali
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
- Department of Biophysics, Panjab University, Chandigarh, India
| | - Paramvir Kaur
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Atul Kumar Goyal
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
- Department of Otolaryngology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Deepak Kumar Pal
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Harshita Arvind
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Khushboo Jindal
- Department of Bioinformatics, Jaypee University, Shimla, India
| | - Vincy Garg
- Department of Cardiology, Swami Vivekananda Yoga Anusandhana Samsthana, Union Territory (SVYASA), Bengaluru, India
| | - Bandu Matyal
- Department of Zoology, Panjab University, Chandigarh, India
| | - Neha Thakur
- Department of Zoology, Panjab University, Chandigarh, India
| | - Amit Chhikara
- Department of Physical Education, Panjab University, Chandigarh, India
| | - Navneet Kaur
- Department of Physical Education, Panjab University, Chandigarh, India
| | - Preety Maanju
- Department of Physical Education, Panjab University, Chandigarh, India
| | | | | | | | - Neeru Malik
- Department of Physical Education, Dev Samaj College of Education, Chandigarh, India
| | - Rakesh Malik
- Department of Physical Education and Sports, Panjab University, Chandigarh, India
| | | | - Ravneet Kaur
- Department of Zoology, Panjab University, Chandigarh, India
| | - Vinod Bhatt
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashish Bhalla
- Department of Internal Medicine, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Manju Mohanty
- Department of Neurosurgery, Post-graduate Institute of Medical Education and Research, Chandigarh, India
| | - Gurmeet Singh
- Department of Physical Education, Panjab University, Chandigarh, India
| | - Suresh Kumar Sharma
- Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh, India
- Department of Statistics, Panjab University, Chandigarh, India
| | - Madhava Sai Sivapuram
- Dr. Pinnamaneni Siddhartha Institute of Medical Sciences and Research Foundation, Vijayawada, India
| | - Deepali Mathur
- School of Biotechnology, KIIT University, Bhubaneswar, India
| | - Dibbendu Khanra
- Department of Cardiology, All India Institute of Medical Sciences, Virbhadra Marg, Rishikesh, India
| | - Akshay Anand
- Neuroscience Research Lab, Department of Neurology, Post-graduate Institute of Medical Education and Research, Chandigarh, India
- *Correspondence: Akshay Anand
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Ondaro J, Hernandez-Eguiazu H, Garciandia-Arcelus M, Loera-Valencia R, Rodriguez-Gómez L, Jiménez-Zúñiga A, Goikolea J, Rodriguez-Rodriguez P, Ruiz-Martinez J, Moreno F, Lopez de Munain A, Holt IJ, Gil-Bea FJ, Gereñu G. Defects of Nutrient Signaling and Autophagy in Neurodegeneration. Front Cell Dev Biol 2022; 10:836196. [PMID: 35419363 PMCID: PMC8996160 DOI: 10.3389/fcell.2022.836196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/21/2022] [Indexed: 12/27/2022] Open
Abstract
Neurons are post-mitotic cells that allocate huge amounts of energy to the synthesis of new organelles and molecules, neurotransmission and to the maintenance of redox homeostasis. In neurons, autophagy is not only crucial to ensure organelle renewal but it is also essential to balance nutritional needs through the mobilization of internal energy stores. A delicate crosstalk between the pathways that sense nutritional status of the cell and the autophagic processes to recycle organelles and macronutrients is fundamental to guarantee the proper functioning of the neuron in times of energy scarcity. This review provides a detailed overview of the pathways and processes involved in the balance of cellular energy mediated by autophagy, which when defective, precipitate the neurodegenerative cascade of Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis or Alzheimer's disease.
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Affiliation(s)
- Jon Ondaro
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Haizea Hernandez-Eguiazu
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Maddi Garciandia-Arcelus
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Raúl Loera-Valencia
- Department of Neurology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden
| | - Laura Rodriguez-Gómez
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Andrés Jiménez-Zúñiga
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Julen Goikolea
- Department of Neurology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden
| | - Patricia Rodriguez-Rodriguez
- Department of Neurology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden
| | - Javier Ruiz-Martinez
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Donostia University Hospital, San Sebastian, Spain
| | - Fermín Moreno
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Donostia University Hospital, San Sebastian, Spain
| | - Adolfo Lopez de Munain
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Donostia University Hospital, San Sebastian, Spain
| | - Ian James Holt
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom
- IKERBASQUE Basque Foundation for Science, Bilbao, Spain
| | - Francisco Javier Gil-Bea
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Gorka Gereñu
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country (UPV-EHU), Leioa, Spain
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Menden A, Hall D, Hahn-Townsend C, Broedlow CA, Joshi U, Pearson A, Crawford F, Evans JE, Klatt N, Crynen S, Mullan M, Ait-Ghezala G. Exogenous lipase administration alters gut microbiota composition and ameliorates Alzheimer's disease-like pathology in APP/PS1 mice. Sci Rep 2022; 12:4797. [PMID: 35314754 PMCID: PMC8938460 DOI: 10.1038/s41598-022-08840-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 03/03/2022] [Indexed: 02/07/2023] Open
Abstract
Alzheimer's disease (AD) represents the most common form of dementia in the elderly with no available disease modifying treatments. Altered gut microbial composition has been widely acknowledged as a common feature of AD, which potentially contributes to progression or onset of AD. To assess the hypothesis that Candida rugosa lipase (CRL), which has been shown to enhance gut microbiome and metabolite composition, can rebalance the gut microbiome composition and reduce AD pathology, the treatment effects in APPswe/PS1de9 (APP/PS1) mice were investigated. The analysis revealed an increased abundance of Acetatifactor and Clostridiales vadin BB60 genera in the gut; increased lipid hydrolysis in the gut lumen, normalization of peripheral unsaturated fatty acids, and reduction of neuroinflammation and memory deficits post treatment. Finally, we demonstrated that the evoked benefits on memory could be transferred via fecal matter transplant (FMT) into antibiotic-induced microbiome-depleted (AIMD) wildtype mice, ameliorating their memory deficits. The findings herein contributed to improve our understanding of the role of the gut microbiome in AD's complex networks and suggested that targeted modification of the gut could contribute to amelioration of AD neuropathology.
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Affiliation(s)
- Ariane Menden
- Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA.
- Open University, Walton Hall, Kents Hill, Milton-Keynes, MK7 6AA, UK.
| | - Davane Hall
- Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA
| | | | - Courtney A Broedlow
- Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN, 55455, USA
| | - Utsav Joshi
- Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA
| | - Andrew Pearson
- Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA
- Open University, Walton Hall, Kents Hill, Milton-Keynes, MK7 6AA, UK
| | - Fiona Crawford
- Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA
- Open University, Walton Hall, Kents Hill, Milton-Keynes, MK7 6AA, UK
- James A. Haley Veterans' Hospital, 13000 Bruce B. Downs Boulevard, Tampa, FL, 33612, USA
| | - James E Evans
- Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA
| | - Nichole Klatt
- Division of Surgical Outcomes and Precision Medicine Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN, 55455, USA
| | - Stefan Crynen
- Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA
- Open University, Walton Hall, Kents Hill, Milton-Keynes, MK7 6AA, UK
| | - Michael Mullan
- Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA
- Open University, Walton Hall, Kents Hill, Milton-Keynes, MK7 6AA, UK
| | - Ghania Ait-Ghezala
- Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA
- Open University, Walton Hall, Kents Hill, Milton-Keynes, MK7 6AA, UK
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Yao S, Xu Z, Chen S, Meng Y, Xue Y, Yao W, Gao X. Silk fibroin hydrolysate improves memory impairment via multi-target function. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.104942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Jeremic D, Jiménez-Díaz L, Navarro-López JD. Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer's disease: a systematic review. Ageing Res Rev 2021; 72:101496. [PMID: 34687956 DOI: 10.1016/j.arr.2021.101496] [Citation(s) in RCA: 139] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/30/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD is still puzzling, and new drugs development and clinical trials have high failure rates. Urgent outline of an integral (multi-target) and effective treatment of AD is needed. Accumulation of amyloid-β (Aβ) peptides is considered one of the fundamental neuropathological pillars of the disease, and its dyshomeostasis has shown a crucial role in AD onset. Therefore, many amyloid-targeted therapies have been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up and review studies focused on anti-amyloid strategies to summarize and analyze their current clinical potential. Combination of anti-Aβ therapies with new developing early detection biomarkers and other therapeutic agents acting on early functional AD changes will be highlighted in this review. Near-term approval seems likely for several drugs acting against Aβ, with recent FDA approval of a monoclonal anti-Aβ oligomers antibody -aducanumab- raising hopes and controversies. We conclude that, development of oligomer-epitope specific Aβ treatment and implementation of multiple improved biomarkers and risk prediction methods allowing early detection, together with therapies acting on other factors such as hyperexcitability in early AD, could be the key to slowing this global pandemic.
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Lin JZ, Duan MR, Lin N, Zhao WJ. The emerging role of the chondroitin sulfate proteoglycan family in neurodegenerative diseases. Rev Neurosci 2021; 32:737-750. [PMID: 33655733 DOI: 10.1515/revneuro-2020-0146] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/07/2021] [Indexed: 02/05/2023]
Abstract
Chondroitin sulfate (CS) is a kind of linear polysaccharide that is covalently linked to proteins to form proteoglycans. Chondroitin sulfate proteoglycans (CSPGs) consist of a core protein, with one or more CS chains covalently attached. CSPGs are precisely regulated and they exert a variety of physiological functions by binding to adhesion molecules and growth factors. Widely distributed in the nervous system in human body, CSPGs contribute to the major component of extracellular matrix (ECM), where they play an important role in the development and maturation of the nervous system, as well as in the pathophysiological response to damage to the central nervous system (CNS). While there are more than 30 types of CSPGs, this review covers the roles of the most important ones, including versican, aggrecan, neurocan and NG2 in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. The updated reports of the treatment of neurodegenerative diseases are involving CSPGs.
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Affiliation(s)
- Jia-Zhe Lin
- Neurosurgical Department, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
- Center for Neuroscience, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Ming-Rui Duan
- Center for Neuroscience, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Nuan Lin
- Obstetrics and Gynecology Department, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Wei-Jiang Zhao
- Center for Neuroscience, Shantou University Medical College, Shantou 515041, Guangdong, China
- Cell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi 214122, Jiangsu, China
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Ullah R, Park TJ, Huang X, Kim MO. Abnormal amyloid beta metabolism in systemic abnormalities and Alzheimer's pathology: Insights and therapeutic approaches from periphery. Ageing Res Rev 2021; 71:101451. [PMID: 34450351 DOI: 10.1016/j.arr.2021.101451] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 08/12/2021] [Accepted: 08/19/2021] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) is an age-associated, multifactorial neurodegenerative disorder that is incurable. Despite recent success in treatments that partially improve symptomatic relief, they have failed in most clinical trials. Re-holding AD for accurate diagnosis and treatment is widely known as a challenging task. Lack of knowledge of basic molecular pathogenesis might be a possible reason for ineffective AD treatment. Historically, a majority of therapy-based studies have investigated the role of amyloid-β (Aβ peptide) in the central nervous system (CNS), whereas less is known about Aβ peptide in the periphery in AD. In this review, we provide a comprehensive summary of the current understanding of Aβ peptide metabolism (anabolism and catabolism) in the brain and periphery. We show that the abnormal metabolism of Aβ peptide is significantly linked with central-brain and peripheral abnormalities; the interaction between peripheral Aβ peptide metabolism and peripheral abnormalities affects central-brain Aβ peptide metabolism, suggesting the existence of significant communication between these two pathways of Aβ peptide metabolism. This close interaction between the central brain and periphery in abnormal Aβ peptide metabolism plays a key role in the development and progression of AD. In conclusion, we need to obtain a full understanding of the dynamic roles of Aβ peptide at the molecular level in both the brain and periphery in relation to the pathology of AD. This will not only provide new information regarding the complex disease pathology, but also offer potential new clues to improve therapeutic strategies and diagnostic biomarkers for the successful treatment of AD.
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Interactions between dietary patterns and genetic factors in relation to incident dementia among 70-year-olds. Eur J Nutr 2021; 61:871-884. [PMID: 34632537 PMCID: PMC8854136 DOI: 10.1007/s00394-021-02688-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 09/28/2021] [Indexed: 10/28/2022]
Abstract
PURPOSE To investigate potential interactions between dietary patterns and genetic factors modulating risk for Alzheimer's disease (AD) in relation to incident dementia. METHODS Data were derived from the population-based Gothenburg H70 Birth Cohort Studies in Sweden, including 602 dementia-free 70-year-olds (examined 1992-93, or 2000-02; 64% women) followed for incident dementia until 2016. Two factors from a reduced rank regression analysis were translated into dietary patterns, one healthy (e.g., vegetables, fruit, and fish) and one western (e.g., red meat, refined cereals, and full-fat dairy products). Genetic risk was determined by APOE ε4 status and non-APOE AD-polygenic risk scores (AD-PRSs). Gene-diet interactions in relation to incident dementia were analysed with Cox regression models. The interaction p value threshold was < 0.1. RESULTS There were interactions between the dietary patterns and APOE ε4 status in relation to incident dementia (interaction p value threshold of < 0.1), while no evidence of interactions were found between the dietary patterns and the AD-PRSs. Those with higher adherence to a healthy dietary pattern had a reduced risk of dementia among ε4 non-carriers (HR: 0.77; 95% CI: 0.61; 0.98), but not among ε4 carriers (HR: 0.86; CI: 0.63; 1.18). Those with a higher adherence to the western dietary pattern had an increased risk of dementia among ε4 carriers (HR: 1.37; 95% CI: 1.05; 1.78), while no association was observed among ε4 non-carriers (HR: 0.99; CI: 0.81; 1.21). CONCLUSIONS The results of this study suggest that there is an interplay between dietary patterns and APOE ε4 status in relation to incident dementia.
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Akyol S, Ugur Z, Yilmaz A, Ustun I, Gorti SKK, Oh K, McGuinness B, Passmore P, Kehoe PG, Maddens ME, Green BD, Graham SF. Lipid Profiling of Alzheimer's Disease Brain Highlights Enrichment in Glycerol(phospho)lipid, and Sphingolipid Metabolism. Cells 2021; 10:2591. [PMID: 34685570 PMCID: PMC8534054 DOI: 10.3390/cells10102591] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/22/2021] [Accepted: 09/25/2021] [Indexed: 11/16/2022] Open
Abstract
Alzheimer's disease (AD) is reported to be closely linked with abnormal lipid metabolism. To gain a more comprehensive understanding of what causes AD and its subsequent development, we profiled the lipidome of postmortem (PM) human brains (neocortex) of people with a range of AD pathology (Braak 0-6). Using high-resolution mass spectrometry, we employed a semi-targeted, fully quantitative lipidomics profiling method (Lipidyzer) to compare the biochemical profiles of brain tissues from persons with mild AD (n = 15) and severe AD (AD; n = 16), and compared them with age-matched, cognitively normal controls (n = 16). Univariate analysis revealed that the concentrations of 420 lipid metabolites significantly (p < 0.05; q < 0.05) differed between AD and controls. A total of 49 lipid metabolites differed between mild AD and controls, and 439 differed between severe AD and mild AD. Interestingly, 13 different subclasses of lipids were significantly perturbed, including neutral lipids, glycerolipids, glycerophospholipids, and sphingolipids. Diacylglycerol (DAG) (14:0/14:0), triacylglycerol (TAG) (58:10/FA20:5), and TAG (48:4/FA18:3) were the most notably altered lipids when AD and control brains were compared (p < 0.05). When we compare mild AD and control brains, phosphatidylethanolamine (PE) (p-18:0/18:1), phosphatidylserine (PS) (18:1/18:2), and PS (14:0/22:6) differed the most (p < 0.05). PE (p-18:0/18:1), DAG (14:0/14:0), and PS (18:1/20:4) were identified as the most significantly perturbed lipids when AD and mild AD brains were compared (p < 0.05). Our analysis provides the most extensive lipid profiling yet undertaken in AD brain tissue and reveals the cumulative perturbation of several lipid pathways with progressive disease pathology. Lipidomics has considerable potential for studying AD etiology and identifying early diagnostic biomarkers.
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Affiliation(s)
- Sumeyya Akyol
- Metabolomics Department, Beaumont Research Institute, Beaumont Health, Royal Oak, MI 48073, USA; (S.A.); (Z.U.); (A.Y.); (K.O.)
| | - Zafer Ugur
- Metabolomics Department, Beaumont Research Institute, Beaumont Health, Royal Oak, MI 48073, USA; (S.A.); (Z.U.); (A.Y.); (K.O.)
| | - Ali Yilmaz
- Metabolomics Department, Beaumont Research Institute, Beaumont Health, Royal Oak, MI 48073, USA; (S.A.); (Z.U.); (A.Y.); (K.O.)
- William Beaumont School of Medicine, Oakland University, Rochester, MI 48073, USA
| | - Ilyas Ustun
- College of Computing and Digital Media, DePaul University, Chicago, IL 60604, USA; (I.U.); (M.E.M.)
| | | | - Kyungjoon Oh
- Metabolomics Department, Beaumont Research Institute, Beaumont Health, Royal Oak, MI 48073, USA; (S.A.); (Z.U.); (A.Y.); (K.O.)
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si 13620, Gyeonggi-do, Korea
| | - Bernadette McGuinness
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast BT12 6BA, UK; (B.M.); (P.P.)
| | - Peter Passmore
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast BT12 6BA, UK; (B.M.); (P.P.)
| | - Patrick G. Kehoe
- Dementia Research Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS10 5NB, UK;
| | - Michael E. Maddens
- College of Computing and Digital Media, DePaul University, Chicago, IL 60604, USA; (I.U.); (M.E.M.)
| | - Brian D. Green
- Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast BT9 5DL, UK;
| | - Stewart F. Graham
- Metabolomics Department, Beaumont Research Institute, Beaumont Health, Royal Oak, MI 48073, USA; (S.A.); (Z.U.); (A.Y.); (K.O.)
- College of Computing and Digital Media, DePaul University, Chicago, IL 60604, USA; (I.U.); (M.E.M.)
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Tsamou M, Pistollato F, Roggen EL. A Tau-Driven Adverse Outcome Pathway Blueprint Toward Memory Loss in Sporadic (Late-Onset) Alzheimer's Disease with Plausible Molecular Initiating Event Plug-Ins for Environmental Neurotoxicants. J Alzheimers Dis 2021; 81:459-485. [PMID: 33843671 DOI: 10.3233/jad-201418] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The worldwide prevalence of sporadic (late-onset) Alzheimer's disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., Aβ-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors.
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Yang CH, Hakun JG, Roque N, Sliwinski MJ, Conroy DE. Mindful walking and cognition in older adults: A proof of concept study using in-lab and ambulatory cognitive measures. Prev Med Rep 2021; 23:101490. [PMID: 34336559 PMCID: PMC8313589 DOI: 10.1016/j.pmedr.2021.101490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 07/05/2021] [Accepted: 07/10/2021] [Indexed: 11/25/2022] Open
Abstract
Mindfulness practice and walking have been linked individually to sustain cognition in older adults. This early-phase study aimed to establish proof-of-concept by evaluating whether an intervention that integrates light-intensity walking with mindfulness practices shows promising signs of improving cognition in older adults. Participants (N = 25, Mage = 72.4 ± 6.45) were community-dwelling older adults who engaged in a supervised mindful walking program over one month (8 sessions total, 2 sessions per week, 30-minute slow walking containing mindfulness skills). They completed performance-based and subjective ratings of cognitive measures in field before and after two mindful walking bouts using a smartphone app. They also completed in-lab performance-based and self-report cognitive measures at baseline and after the entire program. Controlling for demographics, potential covariates, and time trends, short-term improvements in perceived cognition and processing speed were observed from pre- to post-mindful walking sessions (i.e., 30 min) across multiple ambulatory cognitive measures (Cohen's ds range = 0.46-0.66). Longer-term improvements in processing speed and executive function were observed between baseline and end of the program (i.e., one month) across various performance-based cognitive measures (ds range = 0.43-1.28). No significant changes were observed for other cognitive domains. This early-phase study (Phase IIa) provides preliminary support that mindful walking activity is promising for sustaining cognition in older adults. Our promising findings form the building blocks of evidence needed to advance this intervention to a fully powered randomized controlled trial that examines program efficacy with a comparator. Favorable outcomes will inform the development of this lifestyle behavioral strategy for promoting healthy brain aging in late adulthood.
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Affiliation(s)
- Chih-Hsiang Yang
- Department of Exercise Science, University of South Carolina, USA
| | - Jonathan G. Hakun
- Departments of Neurology, The Pennsylvania State University, USA
- Departments of Psychology, The Pennsylvania State University, USA
| | - Nelson Roque
- Center for Healthy Aging, The Pennsylvania State University, USA
| | - Martin J. Sliwinski
- Center for Healthy Aging, The Pennsylvania State University, USA
- Department of Human Development and Family Studies, The Pennsylvania State University, USA
| | - David E. Conroy
- Department of Kinesiology, The Pennsylvania State University, USA
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Gadhave K, Kumar D, Uversky VN, Giri R. A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy. Med Res Rev 2021; 41:2689-2745. [PMID: 32783388 PMCID: PMC7876169 DOI: 10.1002/med.21719] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 07/13/2020] [Accepted: 07/29/2020] [Indexed: 02/06/2023]
Abstract
The exact molecular mechanisms associated with Alzheimer's disease (AD) pathology continue to represent a mystery. In the past decades, comprehensive data were generated on the involvement of different signaling pathways in the AD pathogenesis. However, the utilization of signaling pathways as potential targets for the development of drugs against AD is rather limited due to the immense complexity of the brain and intricate molecular links between these pathways. Therefore, finding a correlation and cross-talk between these signaling pathways and establishing different therapeutic targets within and between those pathways are needed for better understanding of the biological events responsible for the AD-related neurodegeneration. For example, autophagy is a conservative cellular process that shows link with many other AD-related pathways and is crucial for maintenance of the correct cellular balance by degrading AD-associated pathogenic proteins. Considering the central role of autophagy in AD and its interplay with many other pathways, the finest therapeutic strategy to fight against AD is the use of autophagy as a target. As an essential step in this direction, this comprehensive review represents recent findings on the individual AD-related signaling pathways, describes key features of these pathways and their cross-talk with autophagy, represents current drug development, and introduces some of the multitarget beneficial approaches and strategies for the therapeutic intervention of AD.
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Affiliation(s)
- Kundlik Gadhave
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Himachal Pradesh, 175005, India
| | - Deepak Kumar
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Himachal Pradesh, 175005, India
| | - Vladimir N. Uversky
- Department of Molecular Medicine and Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
- Laboratory of New Methods in Biology, Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow Region, Russia
| | - Rajanish Giri
- School of Basic Sciences, Indian Institute of Technology Mandi, Kamand, Himachal Pradesh, 175005, India
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Sekar S, Viswas RS, Miranzadeh Mahabadi H, Alizadeh E, Fonge H, Taghibiglou C. Concussion/Mild Traumatic Brain Injury (TBI) Induces Brain Insulin Resistance: A Positron Emission Tomography (PET) Scanning Study. Int J Mol Sci 2021; 22:9005. [PMID: 34445708 PMCID: PMC8396497 DOI: 10.3390/ijms22169005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/04/2021] [Accepted: 08/13/2021] [Indexed: 01/07/2023] Open
Abstract
Brain injury/concussion is a growing epidemic throughout the world. Although evidence supports association between traumatic brain injury (TBI) and disturbance in brain glucose metabolism, the underlying molecular mechanisms are not well established. Previously, we reported the release of cellular prion protein (PrPc) from the brain to circulation following TBI. The PrPc level was also found to be decreased in insulin-resistant rat brains. In the present study, we investigated the molecular link between PrPc and brain insulin resistance in a single and repeated mild TBI-induced mouse model. Mild TBI was induced in mice by dropping a weight (~95 g at 1 m high) on the right side of the head. The procedure was performed once and thrice (once daily) for single (SI) and repeated induction (RI), respectively. Micro PET/CT imaging revealed that RI mice showed significant reduction in cortical, hippocampal and cerebellum glucose uptake compared to SI and control. Mice that received RI also showed significant motor and cognitive deficits. In co-immunoprecipitation, the interaction between PrPc, flotillin and Cbl-associated protein (CAP) observed in the control mice brains was disrupted by RI. Lipid raft isolation showed decreased levels of PrPc, flotillin and CAP in the RI mice brains. Based on observation, it is clear that PrPc has an interaction with CAP and the dislodgment of PrPc from cell membranes may lead to brain insulin resistance in a mild TBI mouse model. The present study generated a new insight into the pathogenesis of brain injury, which may result in the development of novel therapy.
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Affiliation(s)
- Sathiya Sekar
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada; (S.S.); (H.M.M.)
| | - Raja Solomon Viswas
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada; (R.S.V.); (E.A.)
| | - Hajar Miranzadeh Mahabadi
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada; (S.S.); (H.M.M.)
| | - Elahe Alizadeh
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada; (R.S.V.); (E.A.)
| | - Humphrey Fonge
- Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada; (R.S.V.); (E.A.)
- Department of Medical Imaging, Royal University Hospital (RUH), Saskatoon, SK S7N 0W8, Canada
| | - Changiz Taghibiglou
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada; (S.S.); (H.M.M.)
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Magi S, Preziuso A, Piccirillo S, Giampieri F, Cianciosi D, Orciani M, Amoroso S. The Neuroprotective Effect of L-Carnitine against Glyceraldehyde-Induced Metabolic Impairment: Possible Implications in Alzheimer's Disease. Cells 2021; 10:cells10082109. [PMID: 34440878 PMCID: PMC8394427 DOI: 10.3390/cells10082109] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 08/12/2021] [Accepted: 08/14/2021] [Indexed: 12/19/2022] Open
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive regression and memory loss. Dysfunctions of both glucose metabolism and mitochondrial dynamics have been recognized as the main upstream events of the degenerative processes leading to AD. It has been recently found that correcting cell metabolism by providing alternative substrates can prevent neuronal injury by retaining mitochondrial function and reducing AD marker levels. Here, we induced an AD-like phenotype by using the glycolysis inhibitor glyceraldehyde (GA) and explored whether L-carnitine (4-N-trimethylamino-3-hydroxybutyric acid, LC) could mitigate neuronal damage, both in SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. We have already reported that GA significantly modified AD marker levels; here we demonstrated that GA dramatically compromised cellular bioenergetic status, as revealed by glycolysis and oxygen consumption rate (OCR) evaluation. We found that LC ameliorated cell survival, improved OCR and ATP synthesis, prevented the loss of the mitochondrial membrane potential (Δψm) and reduced the formation of reactive oxygen species (ROS). Of note, the beneficial effect of LC did not rely on the glycolytic pathway rescue. Finally, we noticed that LC significantly reduced the increase in pTau levels induced by GA. Overall, these findings suggest that the use of LC can promote cell survival in the setting of the metabolic impairments commonly observed in AD. Our data suggest that LC may act by maintaining mitochondrial function and by reducing the pTau level.
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Affiliation(s)
- Simona Magi
- Department of Biomedical Sciences and Public Health, School of Medicine, University “Politecnica delle Marche”, Via Tronto 10/A, 60126 Ancona, Italy; (A.P.); (S.P.); (S.A.)
- Correspondence: ; Tel./Fax: +39-071-220-6040
| | - Alessandra Preziuso
- Department of Biomedical Sciences and Public Health, School of Medicine, University “Politecnica delle Marche”, Via Tronto 10/A, 60126 Ancona, Italy; (A.P.); (S.P.); (S.A.)
| | - Silvia Piccirillo
- Department of Biomedical Sciences and Public Health, School of Medicine, University “Politecnica delle Marche”, Via Tronto 10/A, 60126 Ancona, Italy; (A.P.); (S.P.); (S.A.)
| | - Francesca Giampieri
- Department of Clinical Sciences, School of Medicine, University “Politecnica delle Marche”, Via Tronto 10/A, 60126 Ancona, Italy; (F.G.); (D.C.)
- Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah 21577, Saudi Arabia
| | - Danila Cianciosi
- Department of Clinical Sciences, School of Medicine, University “Politecnica delle Marche”, Via Tronto 10/A, 60126 Ancona, Italy; (F.G.); (D.C.)
| | - Monia Orciani
- Department of Clinical and Molecular Sciences-Histology, School of Medicine, University “Politecnica delle Marche”, Via Tronto 10/A, 60126 Ancona, Italy;
| | - Salvatore Amoroso
- Department of Biomedical Sciences and Public Health, School of Medicine, University “Politecnica delle Marche”, Via Tronto 10/A, 60126 Ancona, Italy; (A.P.); (S.P.); (S.A.)
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Wu HM, Goate AM, O'Reilly PF. Heterogeneous effects of genetic risk for Alzheimer's disease on the phenome. Transl Psychiatry 2021; 11:406. [PMID: 34301914 PMCID: PMC8302633 DOI: 10.1038/s41398-021-01518-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 06/11/2021] [Accepted: 07/01/2021] [Indexed: 12/18/2022] Open
Abstract
Here we report how four major forms of Alzheimer's disease (AD) genetic risk-APOE-ε4, APOE-ε2, polygenic risk and familial risk-are associated with 273 traits in ~500,000 individuals in the UK Biobank. The traits cover blood biochemistry and cell traits, metabolic and general health, psychosocial health, and cognitive function. The difference in the profile of traits associated with the different forms of AD risk is striking and may contribute to heterogenous presentation of the disease. However, we also identify traits significantly associated with multiple forms of AD genetic risk, as well as traits showing significant changes across ages in those at high risk of AD, which may point to their potential roles in AD etiology. Finally, we highlight how survivor effects, in particular those relating to shared risks of cardiovascular disease and AD, can generate associations that may mislead interpretation in epidemiological AD studies. The UK Biobank provides a unique opportunity to powerfully compare the effects of different forms of AD genetic risk on the phenome in the same cohort.
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Affiliation(s)
- Hei Man Wu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
| | - Alison M Goate
- Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, NY, USA
- Department of Neurosciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Paul F O'Reilly
- Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
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Wong LR, Tan EA, Lim MEJ, Shen W, Lian XL, Wang Y, Chen L, Ho PCL. Functional effects of berberine in modulating mitochondrial dysfunction and inflammatory response in the respective amyloidogenic cells and activated microglial cells - In vitro models simulating Alzheimer's disease pathology. Life Sci 2021; 282:119824. [PMID: 34265361 DOI: 10.1016/j.lfs.2021.119824] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/03/2021] [Accepted: 07/07/2021] [Indexed: 12/09/2022]
Abstract
AIM Berberine (BBR) is an alkaloid extracted from Coptidis Rhizoma, also known as Huang-Lian. Huang-Lian has been used extensively in traditional Chinese medicine for the treatment of various diseases, including diabetes and dementia. Because Alzheimer's disease (AD) is a complex disease that involves various pathophysiological changes, the diverse neuroprotective effects of BBR may be useful for improving the brain's energy state at an early stage of the disease. MAIN METHODS We performed extracellular flux and 1H NMR-based metabolic profiling analyses to investigate the effects of BBR on metabolic processes in these cells. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-γ (PPARγ) agonist has been studied extensively for the treatment of AD. We explored the combination dosing effects of BBR and PIO in vitro, then leveraged computational methods to explain the experimental finding. KEY FINDINGS BBR demonstrates potential in modulating the mitochondrial bioenergetics and attenuating dysfunction of the primary energy and glutathione metabolism pathways in an AD cell model. It also suppresses basal respiration and reduces the production of pro-inflammatory cytokines in activated microglial cells. Both experimental and computational observations indicate that BBR and PIO have comparable binding affinities to the PPARγ protein, suggesting both drugs may have some overlapping effects for AD. SIGNIFICANCE BBR exerts beneficial effects on disrupted metabolic processes in amyloidogenic cells and activated microglial cells, which are important for preventing or delaying early-stage disease progression. The choice of BBR or PIO for AD treatment depends on their respective pharmacokinetic profiles, delivery, efficacy and safety, and warrants further study.
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Affiliation(s)
- Ling Rong Wong
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117559, Republic of Singapore
| | - Edwin Aik Tan
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117559, Republic of Singapore
| | - Ming En Joshua Lim
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117559, Republic of Singapore
| | - Wanxiang Shen
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117559, Republic of Singapore
| | - Xin Le Lian
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117559, Republic of Singapore
| | - Yali Wang
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117559, Republic of Singapore
| | - Lu Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, 611137 Chengdu, Sichuan, People's Republic of China.
| | - Paul Chi-Lui Ho
- Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117559, Republic of Singapore.
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Muñoz-Jiménez M, Zaarkti A, García-Arnés JA, García-Casares N. Antidiabetic Drugs in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review. Dement Geriatr Cogn Disord 2021; 49:423-434. [PMID: 33080602 DOI: 10.1159/000510677] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 07/30/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Considering that Alzheimer's disease (AD) and diabetes mellitus share pathophysiological features and AD remains with no cure, antidiabetic drugs like intranasal insulin, glitazones, metformin, and liraglutide are being tested as a potential treatment. OBJECTIVE The aim of this systematic review was to assess the efficacy of antidiabetic drugs in patients with AD, mild cognitive impairment (MCI), or subjective cognitive complaints (SCCs). Cognition was studied as the primary outcome and modulation of AD biomarkers, and imaging was also assessed as a secondary outcome. METHODS We conducted a search in the electronic databases PubMed/MEDLINE, EMBASE, and Scopus seeking clinical trials evaluating the effect on cognition of antidiabetic drugs in patients with AD, MCI, or SCCs. RESULTS A total of 23 articles were found eligible. Intranasal regular insulin improved verbal memory in most studies, especially in apoE4- patients, but results in other cognitive domains were unclear. Detemir improved cognition after 2 months of treatment, but it did not after 4 months. Pioglitazone improved cognition in diabetic patients with AD or MCI in 3 clinical trials, but it is controversial as 2 other studies did not show effect. Metformin and liraglutide showed promising results, but further research is needed as just 2 clinical trials involved each of these drugs. Almost all drugs tested were shown to modulate AD biomarkers and imaging. CONCLUSIONS Intranasal insulin, pioglitazone, metformin, and liraglutide are promising drugs that could be useful in the treatment of AD. However, many questions remain to be answered in future studies, so no particular antidiabetic drug can currently be recommended to treat AD.
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Affiliation(s)
- Mario Muñoz-Jiménez
- Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain
| | - Alí Zaarkti
- Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain
| | - Juan Antonio García-Arnés
- Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain.,Department of Pharmacology, Faculty of Medicine, University of Málaga, Málaga, Spain
| | - Natalia García-Casares
- Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain, .,Centro de Investigaciones, Médico-Sanitarias (C.I.M.ES), University of Málaga, Málaga, Spain, .,Instituto de Investigación, Biomédica de Málaga (I.B.I.M.A.), Málaga, Spain,
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Samuelsson J, Kern S, Zetterberg H, Blennow K, Rothenberg E, Wallengren O, Skoog I, Zettergren A. A Western-style dietary pattern is associated with cerebrospinal fluid biomarker levels for preclinical Alzheimer's disease-A population-based cross-sectional study among 70-year-olds. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2021; 7:e12183. [PMID: 34027029 PMCID: PMC8129853 DOI: 10.1002/trc2.12183] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 03/17/2021] [Accepted: 04/20/2021] [Indexed: 01/21/2023]
Abstract
BACKGROUND Diet may be a modifiable factor for reducing the risk of Alzheimer's disease (AD). Western-style dietary patterns are considered to increase the risk, whereas Mediterranean-style dietary patterns are considered to reduce the risk. An association between diet and AD-related biomarkers have been suggested, but studies are limited. AIM To investigate potential relations between dietary patterns and cerebrospinal fluid (CSF) biomarkers for AD among dementia-free older adults. METHODS Data were derived from the population-based Gothenburg H70 Birth Cohort Studies, Sweden. A total of 269 dementia-free 70-year-olds with dietary and cerebrospinal fluid (CSF) amyloid beta (Aβ42 and Aβ40), total tau (t-tau), and phosphorylated tau (p-tau) data were investigated. Dietary intake was determined by the diet history method, and four dietary patterns were derived by principal component analysis. A Western dietary pattern, a Mediterranean/prudent dietary pattern, a high-protein and alcohol pattern, and a high-total and saturated fat pattern. Logistic regression models, with CSF biomarker pathology (yes/no) as dependent variables, and linear regression models with continuous CSF biomarker levels as dependent variables were performed. The analyses were adjusted for sex, energy intake, body mass index (BMI), educational level, and physical activity level. RESULTS The odds ratio for having total tau pathology (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.02 to 2.01) and preclinical AD (Aβ42 and tau pathology; OR 1.79; 95% CI 1.03 to 3.10) was higher among those with a higher adherence to a Western dietary pattern. There were no other associations between the dietary patterns and CSF biomarkers that remained significant in both unadjusted and adjusted models. DISCUSSION Our findings suggest that higher adherence to a Western dietary pattern may be associated with pathological levels of AD biomarkers in the preclinical phase of AD. These findings can be added to the increasing amount of evidence linking diet with AD and may be useful for future intervention studies investigating dietary intake in relation to AD.
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Affiliation(s)
- Jessica Samuelsson
- Neuropsychiatric Epidemiology UnitDepartment of Psychiatry and NeurochemistryInstitute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of GothenburgGothenburgSweden
| | - Silke Kern
- Neuropsychiatric Epidemiology UnitDepartment of Psychiatry and NeurochemistryInstitute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of GothenburgGothenburgSweden
| | - Henrik Zetterberg
- Clinical Neurochemistry LaboratorySahlgrenska University HospitalMölndalSweden
- Department of Psychiatry and NeurochemistryInstitute of Neuroscience and PhysiologySahlgrenska Academy at the University of GothenburgGothenburgSweden
- UK Dementia Research Institute at UCLLondonUK
- Department of Neurodegenerative DiseaseUCL Institute of NeurologyLondonUK
| | - Kaj Blennow
- Clinical Neurochemistry LaboratorySahlgrenska University HospitalMölndalSweden
- Department of Psychiatry and NeurochemistryInstitute of Neuroscience and PhysiologySahlgrenska Academy at the University of GothenburgGothenburgSweden
| | | | - Ola Wallengren
- Clinical Nutrition UnitSahlgrenska University HospitalGothenburgSweden
| | - Ingmar Skoog
- Neuropsychiatric Epidemiology UnitDepartment of Psychiatry and NeurochemistryInstitute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of GothenburgGothenburgSweden
| | - Anna Zettergren
- Neuropsychiatric Epidemiology UnitDepartment of Psychiatry and NeurochemistryInstitute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of GothenburgGothenburgSweden
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Chung KW. Advances in Understanding of the Role of Lipid Metabolism in Aging. Cells 2021; 10:cells10040880. [PMID: 33924316 PMCID: PMC8068994 DOI: 10.3390/cells10040880] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
During aging, body adiposity increases with changes in the metabolism of lipids and their metabolite levels. Considering lipid metabolism, excess adiposity with increased lipotoxicity leads to various age-related diseases, including cardiovascular disease, cancer, arthritis, type 2 diabetes, and Alzheimer's disease. However, the multifaceted nature and complexities of lipid metabolism make it difficult to delineate its exact mechanism and role during aging. With advances in genetic engineering techniques, recent studies have demonstrated that changes in lipid metabolism are associated with aging and age-related diseases. Lipid accumulation and impaired fatty acid utilization in organs are associated with pathophysiological phenotypes of aging. Changes in adipokine levels contribute to aging by modulating changes in systemic metabolism and inflammation. Advances in lipidomic techniques have identified changes in lipid profiles that are associated with aging. Although it remains unclear how lipid metabolism is regulated during aging, or how lipid metabolites impact aging, evidence suggests a dynamic role for lipid metabolism and its metabolites as active participants of signaling pathways and regulators of gene expression. This review describes recent advances in our understanding of lipid metabolism in aging, including established findings and recent approaches.
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Affiliation(s)
- Ki Wung Chung
- College of Pharmacy, Pusan National University, Busan 46214, Korea
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Zhu L, Hu F, Li C, Zhang C, Hang R, Xu R. Perilipin 4 Protein: an Impending Target for Amyotrophic Lateral Sclerosis. Mol Neurobiol 2021; 58:1723-1737. [PMID: 33242187 DOI: 10.1007/s12035-020-02217-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 11/16/2020] [Indexed: 12/17/2022]
Abstract
The pathogenesis of amyotrophic lateral sclerosis (ALS) might exist some relationships with the abnormal lipidomic metabolisms. Therefore, we observed and analyzed the alteration of perilipin 4 (PLIN 4) distribution in the anterior horns (AH); the central canals (CC) and its surrounding gray matter; the posterior horns (PH); and the anterior, lateral, and posterior funiculus (AF, LF, and PF) of the cervical, thoracic, and lumbar segments, as well as the alteration of PLIN 4 expression in the entire spinal cords at the pre-onset, onset, and progression stages of Tg(SOD1*G93A)1Gur (TG) mice and the same period of wild-type(WT) by fluorescent immunohistochemistry, the Western blot, and the image analysis. Results showed that the PLIN 4 distributions in the spinal AH, CC and its surrounding gray matter, PH, AF, and PF of the cervical, thoracic, and lumbar segments in the TG mice at the pre-onset, onset, and progression stages significantly increased compared with those at the same periods of WT mice; the gray matter was especially significant. No significant changes were detected in the LF. PLIN 4 extensively distributed in the neurons and the proliferation neural cells. The PLIN 4 distributions significantly gradually increased from the pre-onset to onset to progression stages, and significantly correlated with the gradual increase death of neural cells. Total PLIN 4 expression in the spinal cords of TG mice significantly increased from the pre-onset, to onset, and to progression stages compared with that in the WT mice. Our data suggested that the PLIN 4 distribution and expression alterations might participate in the death of neural cells in the pathogenesis of ALS through modulating the lipidomic metabolisms and the neural cell proliferation.
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Affiliation(s)
- Lei Zhu
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang, China
| | - Fan Hu
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang, China
| | - Cheng Li
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang, China
| | - Caixiang Zhang
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang, China
| | - Ruiwen Hang
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang, China
| | - Renshi Xu
- Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang, China.
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Soheili M, Karimian M, Hamidi G, Salami M. Alzheimer's disease treatment: The share of herbal medicines. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:123-135. [PMID: 33953850 PMCID: PMC8061323 DOI: 10.22038/ijbms.2020.50536.11512] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 11/07/2020] [Indexed: 11/25/2022]
Abstract
One of the most frequent forms of dementia in neurological disorders is Alzheimer's disease (AD). It is a chronic neurodegenerative disease characterized by impaired learning and memory. Pathological symptoms as extracellular amyloid-beta (Aβ) plaques and intracellular accumulation of neurofibrillary tangles occur in AD. Due to the aging of the population and increased prevalence of AD, discovery of new therapeutic agents with the highest effectiveness and fewer side effect seems to be necessary. Numerous synthetic medicines such as tacrine, donepezil, galantamine, rivastigmine, memantine, glutathione, ascorbic acid, ubiquinone, ibuprofen, and ladostigil are routinely used for reduction of the symptoms and prevention of disease progression. Nowadays, herbal medicines have attracted popular attention for numerous beneficial effects with little side effects. Lavandula angustifolia, Ginkgo biloba, Melissa officinalis, Crocus sativus, Ginseng, Salvia miltiorrhiza, and Magnolia officinalis have been widely used for relief of symptoms of some neurological disorders. This paper reviews the therapeutic effects of phytomedicines with prominent effects against various factors implicated in the emergence and progression of AD.
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Affiliation(s)
- Masoud Soheili
- Physiology Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Karimian
- Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, Iran
| | - Gholamali Hamidi
- Physiology Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mahmoud Salami
- Physiology Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Natarajan K, Ullgren A, Khoshnood B, Johansson C, Laffita-Mesa JM, Pannee J, Zetterberg H, Blennow K, Graff C. Plasma metabolomics of presymptomatic PSEN1-H163Y mutation carriers: a pilot study. Ann Clin Transl Neurol 2021; 8:579-591. [PMID: 33476461 PMCID: PMC7951103 DOI: 10.1002/acn3.51296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 12/04/2020] [Accepted: 12/10/2020] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND AND OBJECTIVE PSEN1-H163Y carriers, at the presymptomatic stage, have reduced 18 FDG-PET binding in the cerebrum of the brain (Scholl et al., Neurobiol Aging 32:1388-1399, 2011). This could imply dysfunctional energy metabolism in the brain. In this study, plasma of presymptomatic PSEN1 mutation carriers was analyzed to understand associated metabolic changes. METHODS We analyzed plasma from noncarriers (NC, n = 8) and presymptomatic PSEN1-H163Y mutation carriers (MC, n = 6) via untargeted metabolomics using gas and liquid chromatography coupled with mass spectrometry, which identified 1199 metabolites. All the metabolites were compared between MC and NC using univariate analysis, as well as correlated with the ratio of Aβ1-42/A β 1-40 , using Spearman's correlation. Altered metabolites were subjected to Ingenuity Pathway Analysis (IPA). RESULTS Based on principal component analysis the plasma metabolite profiles were divided into dataset A and dataset B. In dataset A, when comparing between presymptomatic MC and NC, the levels of 79 different metabolites were altered. Out of 79, only 14 were annotated metabolites. In dataset B, 37 metabolites were significantly altered between presymptomatic MC and NC and nine metabolites were annotated. In both datasets, annotated metabolites represent amino acids, fatty acyls, bile acids, hexoses, purine nucleosides, carboxylic acids, and glycerophosphatidylcholine species. 1-docosapentaenoyl-GPC was positively correlated, uric acid and glucose were negatively correlated with the ratio of plasma Aβ1-42 /Aβ1-40 (P < 0.05). INTERPRETATION This study finds dysregulated metabolite classes, which are changed before the disease symptom onset. Also, it provides an opportunity to compare with sporadic Alzheimer's Disease. Observed findings in this study need to be validated in a larger and independent Familial Alzheimer's Disease (FAD) cohort.
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Affiliation(s)
- Karthick Natarajan
- Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.,Unit for Hereditary Dementias, Theme Aging, QA12, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - Abbe Ullgren
- Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.,Unit for Hereditary Dementias, Theme Aging, QA12, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - Behzad Khoshnood
- Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.,Unit for Hereditary Dementias, Theme Aging, QA12, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - Charlotte Johansson
- Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.,Unit for Hereditary Dementias, Theme Aging, QA12, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - José M Laffita-Mesa
- Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.,Unit for Hereditary Dementias, Theme Aging, QA12, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - Josef Pannee
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Henrik Zetterberg
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Department of Molecular Neuroscience, UCL Institute of Neurology, London, WC1N 3BG, England
| | - Kaj Blennow
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Caroline Graff
- Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.,Unit for Hereditary Dementias, Theme Aging, QA12, Karolinska University Hospital-Solna, Stockholm, Sweden
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A Rationale for Hypoxic and Chemical Conditioning in Huntington's Disease. Int J Mol Sci 2021; 22:ijms22020582. [PMID: 33430140 PMCID: PMC7826574 DOI: 10.3390/ijms22020582] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/23/2020] [Accepted: 01/05/2021] [Indexed: 12/17/2022] Open
Abstract
Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington’s disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington’s disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington’s disease from this knowledge base.
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Langbehn KE, Carlson-Stadler Z, van der Plas E, Hefti MM, Dawson JD, Moser DJ, Nopoulos PC. DMPK mRNA Expression in Human Brain Tissue Throughout the Lifespan. NEUROLOGY-GENETICS 2020; 7:e537. [PMID: 33575482 PMCID: PMC7862092 DOI: 10.1212/nxg.0000000000000537] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 10/19/2020] [Indexed: 11/15/2022]
Abstract
Objective Myotonic dystrophy is a multisystem disorder caused by a trinucleotide repeat expansion on the myotonic dystrophy protein kinase (DMPK) gene. To determine whether wildtype DMPK expression patterns vary as a function of age, we analyzed DMPK expression in the brain from 99 donors ranging from 5 postconceptional weeks to 80 years old. Methods We used the BrainSpan messenger RNA sequencing and the Yale Microarray data sets, which included brain tissue samples from 42 and 57 donors, respectively. Collectively, donors ranged in age from 5 postconceptional weeks to 80 years old. DMPK expression was normalized for each donor across regions available in both data sets. Restricted cubic spline linear regression models were used to analyze the effects of log-transformed age and sex on normalized DMPK expression data. Results Age was a statistically significant predictor of normalized DMPK expression pattern in the human brain in the BrainSpan (p < 0.005) and Yale data sets (p < 0.005). Sex was not a significant predictor. Across both data sets, normalized wildtype DMPK expression steadily increases during fetal development, peaks around birth, and then declines to reach a nadir around age 10. Conclusions Peak expression of DMPK coincides with a time of dynamic brain development. Abnormal brain DMPK expression due to myotonic dystrophy may have implications for early brain development.
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Affiliation(s)
- Kathleen E Langbehn
- Department of Psychiatry (K.E.L., Z.C.-S., E.v.d.P., D.J.M., and P.C.N.), Department of Pathology (M.M.H.), Department of Pediatrics (P.C.N.), and Department of Neurology (P.C.N.), College of Public Health (J.D.D.), University of Iowa
| | - Zoe Carlson-Stadler
- Department of Psychiatry (K.E.L., Z.C.-S., E.v.d.P., D.J.M., and P.C.N.), Department of Pathology (M.M.H.), Department of Pediatrics (P.C.N.), and Department of Neurology (P.C.N.), College of Public Health (J.D.D.), University of Iowa
| | - Ellen van der Plas
- Department of Psychiatry (K.E.L., Z.C.-S., E.v.d.P., D.J.M., and P.C.N.), Department of Pathology (M.M.H.), Department of Pediatrics (P.C.N.), and Department of Neurology (P.C.N.), College of Public Health (J.D.D.), University of Iowa
| | - Marco M Hefti
- Department of Psychiatry (K.E.L., Z.C.-S., E.v.d.P., D.J.M., and P.C.N.), Department of Pathology (M.M.H.), Department of Pediatrics (P.C.N.), and Department of Neurology (P.C.N.), College of Public Health (J.D.D.), University of Iowa
| | - Jeffrey D Dawson
- Department of Psychiatry (K.E.L., Z.C.-S., E.v.d.P., D.J.M., and P.C.N.), Department of Pathology (M.M.H.), Department of Pediatrics (P.C.N.), and Department of Neurology (P.C.N.), College of Public Health (J.D.D.), University of Iowa
| | - David J Moser
- Department of Psychiatry (K.E.L., Z.C.-S., E.v.d.P., D.J.M., and P.C.N.), Department of Pathology (M.M.H.), Department of Pediatrics (P.C.N.), and Department of Neurology (P.C.N.), College of Public Health (J.D.D.), University of Iowa
| | - Peggy C Nopoulos
- Department of Psychiatry (K.E.L., Z.C.-S., E.v.d.P., D.J.M., and P.C.N.), Department of Pathology (M.M.H.), Department of Pediatrics (P.C.N.), and Department of Neurology (P.C.N.), College of Public Health (J.D.D.), University of Iowa
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Ciudin A, Simó-Servat A, Palmas F, Barahona MJ. Obesidad sarcopénica: un nuevo reto en la clínica práctica. ENDOCRINOL DIAB NUTR 2020; 67:672-681. [PMID: 32565081 DOI: 10.1016/j.endinu.2020.03.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 03/04/2020] [Accepted: 03/18/2020] [Indexed: 12/17/2022]
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