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Abbas K, Mustafa M, Alam M, Habib S, Ahmad W, Adnan M, Hassan MI, Usmani N. Multi-target approach to Alzheimer's disease prevention and treatment: antioxidant, anti-inflammatory, and amyloid- modulating mechanisms. Neurogenetics 2025; 26:39. [PMID: 40167826 DOI: 10.1007/s10048-025-00821-y] [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: 01/12/2025] [Accepted: 03/19/2025] [Indexed: 04/02/2025]
Abstract
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation, neurofibrillary tangles, neuroinflammation, and progressive cognitive decline, posing a significant global health challenge. Growing evidence suggests that dietary polyphenols may reduce the risk and progression of AD through multifaceted neuroprotective mechanisms. Polyphenols regulate amyloid proteostasis by inhibiting β/γ-secretase activity, preventing Aβ aggregation, and enhancing clearance pathways. Their strong antioxidant properties neutralize reactive oxygen species, chelate redox-active metals, and activate cytoprotective enzymes via Nrf2 signaling. This review examines the potential therapeutic targets, signaling pathways, and molecular mechanisms by which dietary polyphenols exert neuroprotective effects in AD, focusing on their roles in modulating amyloid proteostasis, oxidative stress, neuroinflammation, and cerebrovascular health. Polyphenols mitigate neuroinflammation by suppressing NF-κB signaling and upregulating brain-derived neurotrophic factor, supporting neuroplasticity and neurogenesis. They also enhance cerebrovascular health by improving cerebral blood flow, maintaining blood-brain barrier integrity, and modulating angiogenesis. This review examines the molecular and cellular pathways through which polyphenols exert neuroprotective effects, focusing on their antioxidant, anti-inflammatory, and amyloid-modulating roles. We also discuss their influence on key AD pathologies, including Aβ deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Insights from clinical and preclinical studies highlight the potential of polyphenols in preventing or slowing AD progression. Future research should explore personalized dietary strategies that integrate genetic and lifestyle factors to optimize the neuroprotective effects of polyphenols.
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Affiliation(s)
- Kashif Abbas
- Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
| | - Mohd Mustafa
- Department of Biochemistry, J.N. Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh, India
| | - Mudassir Alam
- Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
| | - Safia Habib
- Department of Biochemistry, J.N. Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh, India
| | - Waleem Ahmad
- Department of Medicine, J.N. Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh, India
| | - Mohd Adnan
- Department of Biology, College of Science, University of Ha'Il, Ha'il, Saudi Arabia
| | - Md Imtaiyaz Hassan
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.
| | - Nazura Usmani
- Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
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Mikhailov IG, Mikhailova MS, Shuvaev AN, Gorina YV, Belozor OS. RAGE-Mediated Effects of Formaldehyde in Alzheimer's Disease. BIOCHEMISTRY. BIOKHIMIIA 2025; 90:334-348. [PMID: 40367077 DOI: 10.1134/s0006297924604593] [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: 12/18/2024] [Revised: 02/24/2025] [Accepted: 02/28/2025] [Indexed: 05/16/2025]
Abstract
Alzheimer's disease (AD) remains an incurable pathology with a huge socio-economic impact. One of the known mechanisms of AD pathogenesis is deposition of amyloid plaques as a result of beta-amyloid (Aβ) accumulation. The receptor for glycation end products (RAGE) plays an important role in the Aβ transport across the blood-brain barrier. Ligand interaction with RAGE regulates the expression of the amyloid precursor protein (APP), which plays a key role in the Aβ accumulation. In this review, we discuss the biochemical mechanisms underlying the toxic effects of exogenous formaldehyde in the hippocampus leading to the insulin resistance development, as well as molecular mechanisms of neuroinflammation contributing to the upregulation of RAGE expression. Accumulation of endogenous formaldehyde in the body can be a result of impaired metabolism. However, accumulation of exogenous formaldehyde has much more acute and dangerous consequences. Formaldehyde is one of the most important toxins; its maximum permissible concentration (MPC) is exceeded in many cities of Russia, as well as in the countries of East, South, and Southeast Asia, Central Africa, and North and South Americas. Formaldehyde plays an important role in the pathogenesis of neurodegenerative diseases, as its mechanism of action is closely linked to the increased Aβ accumulation. In people more susceptible to Aβ accumulation (due to age or genetic predisposition), exposure to exogenous formaldehyde may contribute to this process. The role of formaldehyde in neurodegenerative diseases has been already investigated. It was found that the level of air pollution correlates with the incidence of hyperglycemia, but the detailed mechanism of the following development of neurodegeneration remains unclear. This review highlights the importance of studying the relationship between environmental toxins and neurodegenerative diseases, which may lead to the development of therapeutic approaches for the protection of neurons from the effects of toxic substances in individuals susceptible to neurodegenerative diseases.
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Affiliation(s)
- Ilya G Mikhailov
- Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, 660022, Russia.
- Siberian Federal University, Krasnoyarsk, 660041, Russia
| | - Milana S Mikhailova
- Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, 660022, Russia
| | - Anton N Shuvaev
- Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, 660022, Russia
| | - Yana V Gorina
- Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, 660022, Russia
| | - Olga S Belozor
- Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, 660022, Russia
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Thapa K, Khan H, Chahuan S, Dhankhar S, Kaur A, Garg N, Saini M, Singh TG. Insights into therapeutic approaches for the treatment of neurodegenerative diseases targeting metabolic syndrome. Mol Biol Rep 2025; 52:260. [PMID: 39982557 DOI: 10.1007/s11033-025-10346-0] [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: 08/01/2024] [Accepted: 02/06/2025] [Indexed: 02/22/2025]
Abstract
Due to the significant energy requirements of nerve cells, glucose is rapidly oxidized to generate ATP and works in conjunction with mitochondria in metabolic pathways, resulting in a combinatorial impact. The purpose of this review is to show how glucose metabolism disorder invariably disrupts the normal functioning of neurons, a phenomenon commonly observed in neurodegenerative diseases. Interventions in these systems may alleviate the degenerative load on neurons. Research on the concepts of metabolic adaptability during disease progression has become a key focus. The majority of the existing treatments are effective in mitigating some clinical symptoms, but they are unsuccessful in preventing neurodegeneration. Hence, there is an urgent need for breakthrough and highly effective therapies for neurodegenerative diseases. Here, we summarise the interactions that various neurodegenerative diseases have with abnormalities in insulin signalling, lipid metabolism, glucose control, and mitochondrial bioenergetics. These factors have a crucial role in brain activity and cognition, and also significantly contribute to neuronal degeneration in pathological conditions. In this article, we have discussed the latest and most promising treatment methods, ranging from molecular advancements to clinical trials, that aim at improving the stability of neurons.
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Affiliation(s)
- Komal Thapa
- Chitkara School of Pharmacy, Chitkara University, Himachal Pradesh, 174103, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Samrat Chahuan
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Sanchit Dhankhar
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Amarjot Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Nitika Garg
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Monika Saini
- M. M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, 133206, India
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Velloso LA, Donato J. Growth Hormone, Hypothalamic Inflammation, and Aging. J Obes Metab Syndr 2024; 33:302-313. [PMID: 39639711 PMCID: PMC11704225 DOI: 10.7570/jomes24032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 09/26/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024] Open
Abstract
While inflammation is a crucial response in injury repair and tissue regeneration, chronic inflammation is a prevalent feature in various chronic, non-communicable diseases such as obesity, diabetes, and cancer and in cardiovascular and neurodegenerative diseases. Long-term inflammation considerably affects disease prevalence, quality of life, and longevity. Our research indicates that the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is a pivotal regulator of inflammation in some tissues, including the hypothalamus, which is a key player in systemic metabolism regulation. Moreover, the GH/IGF-1 axis is strongly linked to longevity, as GH- or GH receptor-deficient mice live approximately twice as long as wild-type animals and exhibit protection against aging-induced inflammation. Conversely, GH excess leads to increased neuroinflammation and reduced longevity. Our review studies the associations between the GH/IGF-1 axis, inflammation, and aging, with a particular focus on evidence suggesting that GH receptor signaling directly induces hypothalamic inflammation. This finding underscores the significant impact of changes in the GH axis on metabolism and on the predisposition to chronic, non-communicable diseases.
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Affiliation(s)
- Licio A. Velloso
- Laboratory of Cell Signalling-Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Campinas, Brazil
| | - Jose Donato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
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Barbut D, Perni M, Zasloff M. Anti-aging properties of the aminosterols of the dogfish shark. NPJ AGING 2024; 10:62. [PMID: 39702521 DOI: 10.1038/s41514-024-00188-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 11/29/2024] [Indexed: 12/21/2024]
Abstract
The development of anti-aging drugs is challenged by both the apparent complexity of the physiological mechanisms involved in aging and the likelihood that many of these mechanisms remain unknown. As a consequence, the development of anti-aging compounds based on the rational targeting of specific pathways has fallen short of the goal. To date, the most impressive compound is rapamycin, a natural bacterial product initially identified as an antifungal, and only subsequently discovered to have anti-aging properties. In this review, we focus on two aminosterols from the dogfish shark, Squalus acanthias, that we discovered initially as broad-spectrum anti-microbial agents. This review is the first to gather together published studies conducted both in vitro and in numerous vertebrate species to demonstrate that these compounds target aging pathways at the cellular level and provide benefits in multiple aging-associated conditions in relevant animal models and in humans. The dogfish aminosterols should be recognized as potential anti-aging drugs.
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Affiliation(s)
- Denise Barbut
- BAZ Therapeutics, Inc., Philadelphia, PA, 19103, USA
| | - Michele Perni
- BAZ Therapeutics, Inc., Philadelphia, PA, 19103, USA
| | - Michael Zasloff
- BAZ Therapeutics, Inc., Philadelphia, PA, 19103, USA.
- MedStar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC, 20010, USA.
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Yanai H, Adachi H, Hakoshima M, Katsuyama H. Pathology and Treatments of Alzheimer's Disease Based on Considering Changes in Brain Energy Metabolism Due to Type 2 Diabetes. Molecules 2024; 29:5936. [PMID: 39770025 PMCID: PMC11677283 DOI: 10.3390/molecules29245936] [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: 10/22/2024] [Revised: 11/22/2024] [Accepted: 12/12/2024] [Indexed: 01/04/2025] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cognitive dysfunction, memory decline, and behavioral disturbance, and it is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Although various hypotheses have been proposed to explain the pathogenesis of AD, including the amyloid beta hypothesis, oxidative stress hypothesis, and abnormal phosphorylation of tau proteins, the exact pathogenic mechanisms underlying AD remain largely undefined. Furthermore, effective curative treatments are very limited. Epidemiologic studies provide convincing evidence for a significant association between type 2 diabetes and AD. Here, we showed energy metabolism using glucose, lactate, ketone bodies, and lipids as energy substrates in a normal brain, and changes in such energy metabolism due to type 2 diabetes. We also showed the influences of such altered energy metabolism due to type 2 diabetes on the pathology of AD. Furthermore, we comprehensively searched for risk factors related with type 2 diabetes for AD and showed possible therapeutic interventions based on considering risk factors and altered brain energy metabolism due to type 2 diabetes for the development of AD.
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Affiliation(s)
- Hidekatsu Yanai
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa 272-8516, Chiba, Japan; (H.A.); (M.H.); (H.K.)
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Da Conceicao AR, Vieira MN, De Felice FG. Structural changes in the obese brain. Neural Regen Res 2024; 19:2561-2562. [PMID: 38808981 PMCID: PMC11168520 DOI: 10.4103/nrr.nrr-d-23-01123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 09/16/2023] [Accepted: 02/08/2024] [Indexed: 05/30/2024] Open
Affiliation(s)
- Anna R.R. Da Conceicao
- D’Or Institute for Research and Education, Rio de Janeiro, Brazil
- Institute of Medical Biochemistry Leopoldo De Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Fernanda G. De Felice
- D’Or Institute for Research and Education, Rio de Janeiro, Brazil
- Institute of Medical Biochemistry Leopoldo De Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences & Department of Psychiatry, Queen’s University, Kingston, ON, Canada
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Wu M, Cheng Y, Zhang R, Han W, Jiang H, Bi C, Zhang Z, Ye M, Lin X, Liu Z. Molecular mechanism and therapeutic strategy of bile acids in Alzheimer's disease from the emerging perspective of the microbiota-gut-brain axis. Biomed Pharmacother 2024; 178:117228. [PMID: 39088965 DOI: 10.1016/j.biopha.2024.117228] [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: 04/21/2024] [Revised: 07/19/2024] [Accepted: 07/28/2024] [Indexed: 08/03/2024] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-β outside neurons and Tau protein inside neurons. Various pathological mechanisms are implicated in AD, including brain insulin resistance, neuroinflammation, and endocrinal dysregulation of adrenal corticosteroids. These factors collectively contribute to neuronal damage and destruction. Recently, bile acids (BAs), which are metabolites of cholesterol, have shown neuroprotective potential against AD by targeting the above pathological changes. BAs can enter the systematic circulation and cross the blood-brain barrier, subsequently exerting neuroprotective effects by targeting several endogenous receptors. Additionally, BAs interact with the microbiota-gut-brain (MGB) axis to improve immune and neuroendocrine function during AD episodes. Gut microbes impact BA signaling in the brain through their involvement in BA biotransformation. In this review, we summarize the role and molecular mechanisms of BAs in AD while considering the MGB axis and propose novel strategies for preventing the onset and progression of AD.
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Affiliation(s)
- Menglu Wu
- Clinical Laboratory, Shaoxing Seventh People's Hospital (Affiliated Mental Health Center, Medical College of Shaoxing University), Shaoxing, Zhejiang, China; Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Yongyi Cheng
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Ruolin Zhang
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Wenwen Han
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Hanqi Jiang
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Chenchen Bi
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Ziyi Zhang
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China
| | - Mengfei Ye
- Department of Psychiatry, Shaoxing Seventh People's Hospital (Affiliated Mental Health Center, Medical College of Shaoxing University), Shaoxing, Zhejiang, China
| | - Xiuqin Lin
- Clinical Laboratory, Shaoxing Seventh People's Hospital (Affiliated Mental Health Center, Medical College of Shaoxing University), Shaoxing, Zhejiang, China.
| | - Zheng Liu
- Department of Behavioral Neurosciences, Science Research Center of Medical School, Shaoxing University, Shaoxing, Zhejiang, China; Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, China.
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Hierro-Bujalance C, Garcia-Alloza M. Empagliflozin reduces brain pathology in Alzheimer's disease and type 2 diabetes. Neural Regen Res 2024; 19:1189-1190. [PMID: 37905858 PMCID: PMC11467955 DOI: 10.4103/1673-5374.385865] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/20/2023] [Accepted: 08/20/2023] [Indexed: 11/02/2023] Open
Affiliation(s)
- Carmen Hierro-Bujalance
- Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain
- Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain
- Salus Infirmorum-Universidad de Cadiz, Cadiz, Spain
| | - Monica Garcia-Alloza
- Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain
- Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain
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Loan A, Syal C, Lui M, He L, Wang J. Promising use of metformin in treating neurological disorders: biomarker-guided therapies. Neural Regen Res 2024; 19:1045-1055. [PMID: 37862207 PMCID: PMC10749596 DOI: 10.4103/1673-5374.385286] [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: 02/09/2023] [Revised: 04/25/2023] [Accepted: 07/29/2023] [Indexed: 10/22/2023] Open
Abstract
Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases (Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease), cerebrovascular conditions (stroke), and neurodevelopmental disorders (autism spectrum disorder). Although they affect millions of individuals around the world, only a limited number of effective treatment options are available today. Since most neurological disorders express mitochondria-related metabolic perturbations, metformin, a biguanide type II antidiabetic drug, has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism. However, controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders. Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging, lifestyle, genetics, and environment, it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders. These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment, ultimately developing targeted therapy. In this review, we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.
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Affiliation(s)
- Allison Loan
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON, Canada
| | - Charvi Syal
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Margarita Lui
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Ling He
- Department of Pediatrics and Medicine, Johns Hopkins Medical School, Baltimore, MD, USA
| | - Jing Wang
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
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Wang F, Li H, Kong T, Shan L, Guo J, Wu Y, Luo X, Satyanarayanan SK, Su K, Liu Y. Association of cigarette smoking with cerebrospinal fluid biomarkers of insulin sensitivity and neurodegeneration. Brain Behav 2024; 14:e3432. [PMID: 38361318 PMCID: PMC10869886 DOI: 10.1002/brb3.3432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/25/2024] [Accepted: 01/27/2024] [Indexed: 02/17/2024] Open
Abstract
INTRODUCTION Cigarette smoking increases both the risk for insulin resistance and amyloid-β (Aβ) aggregation, and impaired brain insulin/insulin-like growth factor 1 (IGF1) signaling might increase risk factors for Alzheimer's disease (AD). We aimed to investigate the association among cerebrospinal fluid (CSF) insulin sensitivity/IGF1, glucose/lactate, and Aβ42 and further explore whether insulin sensitivity contributed to the risk for AD in active smokers. METHODS In this cross-sectional study, levels of insulin, IGF1, and lactate/glucose of 75 active smokers and 78 nonsmokers in CSF were measured. Three polymorphisms regulating IGF1 were genotyped. Analysis of variance was used to compare differences of variables between groups. Partial correlation was performed to test the relationship between CSF biomarkers and smoking status. General linear models were applied to test the interaction of the effect of single nucleotide polymorphisms and cigarette smoking on CSF IGF1 levels. RESULTS In the CSF from active smokers, IGF1 and lactate levels were significantly lower (p = .016 and p = .010, respectively), whereas Aβ42 (derived from our earlier research) and insulin levels were significantly higher (p < .001 and p = .022, respectively) as compared to the CSF from nonsmokers. The AG + GG genotype of rs6218 in active smokers had a significant effect on lower CSF IGF1 levels (p = .004) and lower CSF insulin levels in nonsmokers (p = .016). CONCLUSIONS Cigarette smoking as the "at-risk" factor for AD might be due to lower cerebral insulin sensitivity in CSF, and the subjects with rs6218G allele seem to be more susceptible to the neurodegenerative risks for cigarette smoking.
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Grants
- QML20212003 "Qingmiao" program of Beijing Municipal Hospital Management Center
- LY202106 Youth Scientific Research Foundation of Beijing Huilongguan Hospital
- 2017Q007 Tianshan Youth Project-Outstanding Youth Science and Technology Talents of Xinjiang
- 2022J0112 Natural Science Foundation of Fujian Province
- ANHRF109-31 The 10th Inner Mongolia Autonomous Region 'Prairie excellence' Project, the An Nan Hospital, China Medical University, Tainan, Taiwan
- 110-13 The 10th Inner Mongolia Autonomous Region 'Prairie excellence' Project, the An Nan Hospital, China Medical University, Tainan, Taiwan
- 110-26 The 10th Inner Mongolia Autonomous Region 'Prairie excellence' Project, the An Nan Hospital, China Medical University, Tainan, Taiwan
- 2017E0267 The technology support project of xinjiang
- 7152074 Beijing Natural Science Foundation
- 2017D01C245 Natural Science Foundation of Xinjiang Province
- 2018D01C228 Natural Science Foundation of Xinjiang Province
- 2019D01C229 Natural Science Foundation of Xinjiang Province
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Affiliation(s)
- Fan Wang
- Beijing Huilongguan HospitalPeking UniversityBeijingChina
| | - Hui Li
- Department of Biomedical EngineeringCollege of Future TechnologyPeking UniversityBeijingChina
| | - Tiantian Kong
- Xinjiang Key Laboratory of Neurological Disorder Researchthe Second Affiliated Hospital of Xinjiang Medical UniversityUrumqiChina
| | - Ligang Shan
- Department of Anesthesiologythe Second Affiliated Hospital of Xiamen Medical CollegeXiamenChina
| | - Jiajia Guo
- Medical SectionThe Third Hospital of BaoGang GroupBaotouChina
- The Affiliated Hospital of Inner Mongolia Medical UniversityHuhhotChina
| | - Yan Wu
- Beijing Huilongguan HospitalPeking UniversityBeijingChina
| | - Xingguang Luo
- Department of PsychiatryYale University School of MedicineNew HavenUSA
| | - Senthil Kumaran Satyanarayanan
- Department of Psychiatry & Mind‐Body Interface Laboratory (MBI‐Lab)China Medical University HospitalTaichungTaiwan
- College of MedicineChina Medical UniversityTaichungTaiwan
| | - Kuan‐Pin Su
- Department of Psychiatry & Mind‐Body Interface Laboratory (MBI‐Lab)China Medical University HospitalTaichungTaiwan
- College of MedicineChina Medical UniversityTaichungTaiwan
- An‐Nan HospitalChina Medical UniversityTainanTaiwan
| | - Yanlong Liu
- Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning HospitalWenzhou Medical UniversityWenzhouChina
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Nasb M, Tao W, Chen N. Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses. Aging Dis 2024; 15:43-73. [PMID: 37450931 PMCID: PMC10796101 DOI: 10.14336/ad.2023.0608] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 06/08/2023] [Indexed: 07/18/2023] Open
Abstract
Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by both amnestic and non-amnestic clinical manifestations. It accounts for approximately 60-70% of all dementia cases worldwide. With the increasing number of AD patients, elucidating underlying mechanisms and developing corresponding interventional strategies are necessary. Hypotheses about AD such as amyloid cascade, Tau hyper-phosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic, and vascular hypotheses are not mutually exclusive, and all of them play a certain role in the development of AD. The amyloid cascade hypothesis is currently the most widely studied; however, other hypotheses are also gaining support. This article summarizes the recent evidence regarding major pathological hypotheses of AD and their potential interplay, as well as the strengths and weaknesses of each hypothesis and their implications for the development of effective treatments. This could stimulate further studies and promote the development of more effective therapeutic strategies for AD.
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Affiliation(s)
| | | | - Ning Chen
- Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring, College of Sports Medicine, Wuhan Sports University, Wuhan 430079, China
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Medina-Vera D, López-Gambero AJ, Navarro JA, Sanjuan C, Baixeras E, Decara J, de Fonseca FR. Novel insights into D-Pinitol based therapies: a link between tau hyperphosphorylation and insulin resistance. Neural Regen Res 2024; 19:289-295. [PMID: 37488880 PMCID: PMC10503604 DOI: 10.4103/1673-5374.379015] [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: 03/08/2023] [Revised: 04/21/2023] [Accepted: 05/18/2023] [Indexed: 07/26/2023] Open
Abstract
Alzheimer's disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer's disease. The pathogenesis of Alzheimer's disease is mainly mediated by the phosphorylation and aggregation of tau protein. Among the multiple causes of tau hyperphosphorylation, brain insulin resistance has generated much attention, and inositols as insulin sensitizers, are currently considered candidates for drug development. The present narrative review revises the interactions between these three elements: Alzheimer's disease-tau-inositols, which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.
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Affiliation(s)
- Dina Medina-Vera
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, UGC Salud Mental, Málaga, Spain
- Facultad de Ciencias, Universidad de Málaga, Málaga, Spain
- CIBER Enfermedades Cardiovasculares (CIBERCV), Hospital Universitario Virgen de la Victoria, UGC del Corazón, Málaga, Spain
| | - Antonio Jesús López-Gambero
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, UGC Salud Mental, Málaga, Spain
- Facultad de Ciencias, Universidad de Málaga, Málaga, Spain
- University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France
| | - Juan Antonio Navarro
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, UGC Salud Mental, Málaga, Spain
| | | | - Elena Baixeras
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Málaga, Málaga, Spain
| | - Juan Decara
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, UGC Salud Mental, Málaga, Spain
| | - Fernando Rodríguez de Fonseca
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, UGC Salud Mental, Málaga, Spain
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Guo M, Wang X, Li Y, Luo A, Zhao Y, Luo X, Li S. Intermittent Fasting on Neurologic Diseases: Potential Role of Gut Microbiota. Nutrients 2023; 15:4915. [PMID: 38068773 PMCID: PMC10707790 DOI: 10.3390/nu15234915] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/13/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
As the global population ages, the prevalence of neurodegenerative diseases is surging. These disorders have a multifaceted pathogenesis, entwined with genetic and environmental factors. Emerging research underscores the profound influence of diet on the development and progression of health conditions. Intermittent fasting (IF), a dietary pattern that is increasingly embraced and recommended, has demonstrated potential in improving neurophysiological functions and mitigating pathological injuries with few adverse effects. Although the precise mechanisms of IF's beneficial impact are not yet completely understood, gut microbiota and their metabolites are believed to be pivotal in mediating these effects. This review endeavors to thoroughly examine current studies on the shifts in gut microbiota and metabolite profiles prompted by IF, and their possible consequences for neural health. It also highlights the significance of dietary strategies as a clinical consideration for those with neurological conditions.
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Affiliation(s)
- Mingke Guo
- Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Department of Anesthesiology, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.G.); (X.W.); (Y.L.); (A.L.); (Y.Z.)
| | - Xuan Wang
- Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Department of Anesthesiology, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.G.); (X.W.); (Y.L.); (A.L.); (Y.Z.)
| | - Yujuan Li
- Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Department of Anesthesiology, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.G.); (X.W.); (Y.L.); (A.L.); (Y.Z.)
| | - Ailin Luo
- Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Department of Anesthesiology, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.G.); (X.W.); (Y.L.); (A.L.); (Y.Z.)
| | - Yilin Zhao
- Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Department of Anesthesiology, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.G.); (X.W.); (Y.L.); (A.L.); (Y.Z.)
| | - Xiaoxiao Luo
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shiyong Li
- Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Department of Anesthesiology, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (M.G.); (X.W.); (Y.L.); (A.L.); (Y.Z.)
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15
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Mone P, De Gennaro S, Moriello D, Frullone S, D’Amelio R, Ferrante MNV, Marro A, Santulli G. Insulin resistance drives cognitive impairment in hypertensive pre-diabetic frail elders: the CENTENNIAL study. Eur J Prev Cardiol 2023; 30:1283-1288. [PMID: 37196030 PMCID: PMC10480019 DOI: 10.1093/eurjpc/zwad173] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/27/2023] [Accepted: 05/15/2023] [Indexed: 05/19/2023]
Abstract
AIMS Pre-diabetes is a condition that confers an increased cardiovascular risk. Frailty is very common in hypertensive patients, and insulin resistance has been linked to frailty in older adults with diabetes. On these grounds, our aim was to evaluate the association between insulin resistance and cognitive impairment in hypertensive and pre-diabetic and frail older adults. METHODS AND RESULTS We studied consecutive pre-diabetic and hypertensive elders with frailty presenting at the Avellino local health authority of the Italian Ministry of Health (ASL AV) from March 2021 to March 2022. All of them fulfilled the following inclusion criteria: a previous diagnosis of hypertension with no clinical or laboratory evidence of secondary causes, a confirmed diagnosis of pre-diabetes, age >65 years, Montreal Cognitive Assessment (MoCA) Score <26, and frailty. We enrolled 178 frail patients, of which 141 successfully completed the study. We observed a strong inverse correlation (r = -0.807; P < 0.001) between MoCA Score and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). The results were confirmed by a linear regression analysis using MoCA Score as dependent variable, after adjusting for several potential confounders. CONCLUSION Taken together, our data highlight for the first time the association between insulin resistance and global cognitive function in frail elders with hypertension and pre-diabetes.
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Affiliation(s)
- Pasquale Mone
- Division of Cardiology, Department of Medicine, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research (EIAR), Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York City, NY 10461, USA
- Avellino Local Health Authority of the Italian Ministry of Health (ASL AV), Avellino 83100, Italy
- Department of Medicine and Health Science “V. Tiberio”, Molise University, Campobasso 86100, Italy
| | - Stefano De Gennaro
- Avellino Local Health Authority of the Italian Ministry of Health (ASL AV), Avellino 83100, Italy
| | - Divina Moriello
- Avellino Local Health Authority of the Italian Ministry of Health (ASL AV), Avellino 83100, Italy
| | - Salvatore Frullone
- Avellino Local Health Authority of the Italian Ministry of Health (ASL AV), Avellino 83100, Italy
| | - Rosa D’Amelio
- Avellino Local Health Authority of the Italian Ministry of Health (ASL AV), Avellino 83100, Italy
| | | | - Anna Marro
- Avellino Local Health Authority of the Italian Ministry of Health (ASL AV), Avellino 83100, Italy
| | - Gaetano Santulli
- Division of Cardiology, Department of Medicine, Wilf Family Cardiovascular Research Institute, Einstein Institute for Aging Research (EIAR), Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York City, NY 10461, USA
- International Translational Research and Medical Education (ITME) Consortium, Academic Research Unit, University of Naples “Federico II”, Naples 80131, Italy
- Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Einstein Institute for Institute for Neuroimmunology and Inflammation (INI), Albert Einstein College of Medicine, New York City, NY 10461, USA
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16
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Lanza M, Basilotta R, Cuzzocrea S, Bulzomì M, Oddo S, Casili G, Esposito E. An RNAi-Mediated Reduction in Transcription Factor Nrf-2 Blocks the Positive Effects of Dimethyl Fumarate on Metabolic Stress in Alzheimer's Disease. Int J Mol Sci 2023; 24:11303. [PMID: 37511065 PMCID: PMC10378911 DOI: 10.3390/ijms241411303] [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: 06/08/2023] [Revised: 07/04/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
The prevalence of obesity is rapidly rising around the world, and this will have a significant impact on our society as it is believed to be one of the leading causes of death. One of the main causes of these occurrences is added sugar consumption, which is associated with a higher risk of obesity, heart disease, diabetes, and brain illnesses such as Alzheimer's disease (AD). To this purpose, excess sugar might worsen oxidative damage and brain inflammation: two neuropathological signs of AD. Dimethyl fumarate (DMF) is an orally accessible methyl ester of fumaric acid with putative neuroprotective and immunomodulatory properties. In addition, DMF stimulates the nuclear factor erythroid 2-related factor 2 (Nrf-2), a key regulator of the antioxidant response mechanism in cells. The aim of the current study was to assess the potential therapeutic benefits of DMF in an in vitro model of metabolic stress induced by high and low sugar levels. We discovered that DMF reversed the negative impacts of high and low glucose exposure on the viability and oxidative stress of SH-SY5Y cells. Mechanistically, DMF's actions were mediated by Nrf-2. To this end, we discovered that DMF boosted the expression of the Nrf-2-regulated genes heme-oxygenase-1 (HO1) and manganese superoxide dismutase (MnSOD). More importantly, we found that inhibiting Nrf-2 expression prevented DMF's positive effects. Our combined findings suggest that DMF may be a valuable support for treatments for metabolic diseases.
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Affiliation(s)
- Marika Lanza
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Rossella Basilotta
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Maria Bulzomì
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Salvatore Oddo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Giovanna Casili
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy
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Wasinski F, Tavares MR, Gusmao DO, List EO, Kopchick JJ, Alves GA, Frazao R, Donato J. Central growth hormone action regulates neuroglial and proinflammatory markers in the hypothalamus of male mice. Neurosci Lett 2023; 806:137236. [PMID: 37030549 PMCID: PMC10133206 DOI: 10.1016/j.neulet.2023.137236] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/03/2023] [Accepted: 04/04/2023] [Indexed: 04/10/2023]
Abstract
Growth hormone (GH) action in specific neuronal populations regulates neuroendocrine responses, metabolism, and behavior. However, the potential role of central GH action on glial function is less understood. The present study aims to determine how the hypothalamic expression of several neuroglial markers is affected by central GH action in male mice. The dwarf GH- and insulin-like growth factor-1 (IGF-1)-deficient Ghrhrlit/lit mice showed decreased mRNA expression of Nes (Nestin), Gfap, Iba1, Adgre1 (F4/80), and Tnf (TNFα) in the hypothalamus, compared to wild-type animals. In contrast, transgenic overexpression of GH led to high serum GH and IGF-1 levels, and increased hypothalamic expression of Nes, Gfap, Adgre1, Iba1, and Rax. Hepatocyte-specific GH receptor (GHR) knockout mice, which are characterized by high serum GH levels, but reduced IGF-1 secretion, showed increased mRNA expression of Gfap, Iba1, Tnf, and Sox10, demonstrating that the increase in GH levels alters the hypothalamic expression of glial markers associated with neuroinflammation, independently of IGF-1. Conversely, brain-specific GHR knockout mice showed reduced expression of Gfap, Adgre1, and Vim (vimentin), indicating that brain GHR signaling is necessary to mediate GH-induced changes in the expression of several neuroglial markers. In conclusion, the hypothalamic mRNA levels of several neuroglial markers associated with inflammation are directly modulated by GHR signaling in male mice.
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Affiliation(s)
- Frederick Wasinski
- Department of Neurology and Neurosurgery, Universidade Federal de Sao Paulo, Sao Paulo, SP 04039-032, Brazil
| | - Mariana R Tavares
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP 05508-000, Brazil
| | - Daniela O Gusmao
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP 05508-000, Brazil
| | - Edward O List
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - John J Kopchick
- Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Guilherme A Alves
- Department of Anatomy, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP 05508-900, Brazil
| | - Renata Frazao
- Department of Anatomy, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP 05508-900, Brazil
| | - Jose Donato
- Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP 05508-000, Brazil.
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Cho S, Ok Kim C, Cha BS, Kim E, Mo Nam C, Kim MG, Soo Park M. The effects of long-term cumulative HbA1c exposure on the development and onset time of dementia in the patients with type 2 diabetes mellitus: hospital based retrospective study (2005-2021). Diabetes Res Clin Pract 2023:110721. [PMID: 37196708 DOI: 10.1016/j.diabres.2023.110721] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/05/2023] [Accepted: 05/11/2023] [Indexed: 05/19/2023]
Abstract
AIMS We examine cumulative effect of long-term glycemic exposure in patients with type 2 diabetes mellitus (T2DM) on the development of dementia. METHODS The study involved 20,487 records of patients with T2DM identified in the electronic medical record at Severance Hospital, Korea. Cumulative HbA1c (AUCHbA1c) and mean HbA1c over time (HbA1cavg) as measures of long-term glycemic exposure were compared for the development of dementia and the time to dementia. RESULTS AUCHbA1c and HbA1cavg were significantly higher in patients who later developed dementia than in those who did not dementia (AUCHbA1c: 56.2 ± 26.4 vs. 52.1 ± 26.1 %*Year; HbA1cavg: 7.0 ± 1.0 vs. 7.3 ± 1.0 %). Odds ratio of dementia increased when HbA1cavg was 7.2% (55 mmol/mol) or above, and when AUCHbA1c was 42 %*Year (e.g., HbA1c 7.0% maintained for 6 years) or above. Among those who developed dementia, as HbA1cavg increased, the time to dementia onset decreased (β = -380.6 days, 95% confidence interval [CI]: -416.2 to -345.0). CONCLUSIONS Our results indicate poorly controlled T2DM was associated with an increased risk of developing dementia, as measured by AUCHbA1c and HbA1cavg. Higher cumulative glycemic exposure may lead to developing dementia in a shorter time.
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Affiliation(s)
- Sunyoung Cho
- Department of Pharmaceutical Medicine and Regulatory Sciences, College of Medicine and Pharmacy, Yonsei University, Seoul, Korea.
| | - Choon Ok Kim
- Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea.
| | - Bong-Soo Cha
- Division of Endocrinology, Department of Internal Medicine, Severance Hospital, College of Medicine, Yonsei University, Seoul, Korea.
| | - Eosu Kim
- Department of Psychiatry, Institute of Behavioral Science in Medicine, College of Medicine, Yonsei University, Yonsei University, Seoul, Korea.
| | - Chung Mo Nam
- Department of Preventive Medicine, College of Medicine , Yonsei University, Seoul, Korea.
| | - Min-Gul Kim
- Department of Pharmacology, College of Medicine, Jeonbuk National University, Jeonju, Korea.
| | - Min Soo Park
- Department of Pediatrics, Department of Clinical Pharmacology, Severance Hospital, College of Medicine, Yonsei University, Seoul, Korea.
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19
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Ertas B, Hazar-Yavuz AN, Topal F, Keles-Kaya R, Karakus Ö, Ozcan GS, Taskin T, Cam ME. Rosa canina L. improves learning and memory-associated cognitive impairment by regulating glucose levels and reducing hippocampal insulin resistance in high-fat diet/streptozotocin-induced diabetic rats. JOURNAL OF ETHNOPHARMACOLOGY 2023; 313:116541. [PMID: 37088237 DOI: 10.1016/j.jep.2023.116541] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/20/2023] [Indexed: 05/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Recent studies claim that Type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) overlap in several common pathological pathways which from neuronal damage to impaired memory performance. It is known that the use of Rosa canina L. (R. canina) as medicine in folk medicine dates back to ancient times and is used in the treatment of nervous diseases in Persian medicine. However, the effect of R. canina on diabetes-related cognitive decline and memory impairment has not yet been studied. AIM OF THE STUDY We evaluated the impact of T2DM on AD-like alterations and examined the molecular mechanism of a possible effect of R. canina on cognitive alterations in diabetic rats. MATERIALS&METHODS R. canina ethanol extract was obtained by maceration method. This study was performed with male Spraque-Dawley rats fed with a high-fat diet (HFD) for 8 weeks, low-dose streptozotocin (STZ; 35 mg/kg IP) injection for 4 weeks, and R. canina (250 mg/kg; per oral) and metformin (400 mg/kg; per oral) administration for 4 weeks. The weight and blood glucose of rats were measured weekly. To evaluate glucose tolerance area under the curve (AUC) was calculated by performing an oral glucose tolerance test. Then the rats were subjected to behavioural tests, and their hippocampus and cortex tissues were obtained for biochemical and morphological analyses. RESULTS R. canina could manage glucose responsiveness by reducing post-prandial blood glucose levels, preventing weight loss, and raising serum insulin levels in T2DM-induced rats. Behavioural tests showed that R. canina significantly improves diabetes-related cognitive decline in recall and long-term memory. Treatment with R. canina significantly reversed HFD/STZ-induced increases in insulin, amyloid-β, amyloid precursor protein levels, and acetylcholinesterase activity in the prefrontal cortex and hippocampus. Furthermore, histological analyzes revealed the protection of R. canina against neuronal disruption in the cortical and hippocampal CA3 region caused by chronic hyperglycemia. CONCLUSION Analyzed collectively, these results suggest that R. canina can correct T2DM-related cognitive decline may be attributed to insulin pathway modulation, prevention of amyloid deposition, and increased cholinergic transmission.
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Affiliation(s)
- Busra Ertas
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, Istanbul, 34854, Turkey; Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, 34722, Istanbul, Turkey
| | - Ayse Nur Hazar-Yavuz
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, Istanbul, 34854, Turkey
| | - Fadime Topal
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, Istanbul, 34854, Turkey
| | - Rumeysa Keles-Kaya
- Department of Pharmacology, Faculty of Pharmacy, University of Health Sciences, Istanbul, 34854, Turkey
| | - Özge Karakus
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, Istanbul, 34854, Turkey
| | - Gul Sinemcan Ozcan
- Stem Cell and Gene Therapies Research and Applied Center, Medical Faculty, Kocaeli University, Kocaeli, 41380, Turkey
| | - Turgut Taskin
- Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Istanbul, 34854, Turkey
| | - Muhammet Emin Cam
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, Istanbul, 34854, Turkey; Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, 34722, Istanbul, Turkey; UCL Division of Surgery and Interventional Science, Royal Free Hospital Campus, University College London, Rowland Hill Street, NW3 2PF, UK; Biomedical Engineering Department, University of Aveiro, 3810-193, Aveiro, Portugal; Center for Nanotechnology and Biomaterials Application and Research, Marmara University, Istanbul, 34722, Turkey.
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20
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Prajjwal P, Asharaf S, Makhanasa D, Yamparala A, Tariq H, Aleti S, Gadam S, Vora N. Association of Alzheimer's dementia with oral bacteria, vitamin B12, folate, homocysteine levels, and insulin resistance along with its pathophysiology, genetics, imaging, and biomarkers. Dis Mon 2023; 69:101546. [PMID: 36931946 DOI: 10.1016/j.disamonth.2023.101546] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Alzheimer's disease is a prevalent form of dementia, particularly among the elderly population. It is characterized by progressive cognitive decline and neurodegeneration. Despite numerous studies, the exact cause of Alzheimer's disease remains uncertain, and various theories have been proposed, including Aβ amyloid deposition in the brain and tau protein hyper-phosphorylation. This review article explores the potential pathogenesis of Alzheimer's disease, focusing on the effects of derangements in the levels of vitamin B12, folate, and homocysteine, as well as the impact of oral bacteria causing periodontitis and insulin resistance, and their relationship to Alzheimer's. Studies have shown that high levels of homocysteine and low levels of vitamin B12 and folate, are associated with an increased risk of developing Alzheimer's disease. The article also explores the link between Alzheimer's disease and oral bacteria, specifically dental infections and periodontitis, which contribute to the inflammatory processes in the nervous system of Alzheimer's patients. There could be derangement in the insulin signaling further causing disruption in glucose metabolism within the brain, suggesting that Alzheimer's disease may represent a form of type 2 diabetes mellitus associated with the brain, commonly known as type 3 diabetes. Neuroimaging techniques, including MRI, PET, and tau PET, can identify the predictive characteristics of Alzheimer's disease, with amyloid PET being the most useful in ruling out the disease. The article concludes by stressing the importance of understanding genetic and neuroimaging factors in the diagnosing and treating Alzheimer's disease.
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Affiliation(s)
| | - Shahnaz Asharaf
- Internal Medicine, Travancore Medical College, Kollam, Kerala, India
| | | | | | - Halla Tariq
- Internal Medicine, Multan Medical and Dental College, Multan, Pakistan
| | - Soumya Aleti
- Internal Medicine, Berkshire Medical Center, Pittsfield, MA, USA
| | - Srikanth Gadam
- Internal Medicine, Postdoctoral Research Fellow, Mayo Clinic, USA
| | - Neel Vora
- Internal Medicine, B. J. Medical College, Ahmedabad, India
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21
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Leclerc M, Bourassa P, Tremblay C, Caron V, Sugère C, Emond V, Bennett DA, Calon F. Cerebrovascular insulin receptors are defective in Alzheimer's disease. Brain 2023; 146:75-90. [PMID: 36280236 PMCID: PMC9897197 DOI: 10.1093/brain/awac309] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/24/2022] [Accepted: 08/12/2022] [Indexed: 01/11/2023] Open
Abstract
Central response to insulin is suspected to be defective in Alzheimer's disease. As most insulin is secreted in the bloodstream by the pancreas, its capacity to regulate brain functions must, at least partly, be mediated through the cerebral vasculature. However, how insulin interacts with the blood-brain barrier and whether alterations of this interaction could contribute to Alzheimer's disease pathophysiology both remain poorly defined. Here, we show that human and murine cerebral insulin receptors (INSRs), particularly the long isoform INSRα-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSRα-B were lower in the parietal cortex of subjects diagnosed with Alzheimer's disease, positively correlating with cognitive scores, leading to a shift towards a higher INSRα-A/B ratio, consistent with cerebrovascular insulin resistance in the Alzheimer's disease brain. Vascular INSRα was inversely correlated with amyloid-β plaques and β-site APP cleaving enzyme 1, but positively correlated with insulin-degrading enzyme, neprilysin and P-glycoprotein. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the blood-brain barrier remained very low (<0.03 µl/g·s) and was not inhibited by an insulin receptor antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSRβ that was restricted to microvessels. Such an activation of vascular insulin receptor was blunted in 3xTg-AD mice, suggesting that Alzheimer's disease neuropathology induces insulin resistance at the level of the blood-brain barrier. Overall, the present data in post-mortem Alzheimer's disease brains and an animal model of Alzheimer's disease indicate that defects in the insulin receptor localized at the blood-brain barrier strongly contribute to brain insulin resistance in Alzheimer's disease, in association with β-amyloid pathology.
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Affiliation(s)
- Manon Leclerc
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada
| | - Philippe Bourassa
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - Cyntia Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - Vicky Caron
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - Camille Sugère
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - Vincent Emond
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
| | - David A Bennett
- Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL 60612, USA
| | - Frédéric Calon
- Faculté de Pharmacie, Université Laval, Québec, QC G1V 0A6, Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Quebec, QC G1V 4G2, Canada
- Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Québec, QC G1V 0A6, Canada
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22
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Liu CC, Wang QH, Xin JY, Liu YH, Zeng F, Chen DW, Li HY, Yi X, Zeng GH, Wang YJ, Xiang Y, Chen Y. Association of Adipokines with Alzheimer's Disease in a Chinese Cohort. J Alzheimers Dis 2023; 96:523-533. [PMID: 37807776 DOI: 10.3233/jad-220860] [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: 10/10/2023]
Abstract
BACKGROUND The correlation between plasma adipose factor levels and Alzheimer's patients is not entirely clear. OBJECTIVE We aimed to investigate associations between AD and plasma levels of three adipokines including plasma adiponectin, leptin, and resistin. METHODS A single-center, cross-sectional study recruited AD patients (n = 148) and cognitively normal (CN) controls (n = 110). The multivariate logistic regression analysis was applied to determine associations of adiponectin, leptin, and resistin with the presence of AD. The receiver operating characteristic (ROC) analysis was employed to determine the diagnostic power of adiponectin, leptin and resistin for AD. RESULTS After adjusted for the conventional risk factors, plasma levels of leptin (OR = 0.417, 95% CI: 0.272-0.638, p < 0.0001) and adiponectin (OR = 1.249, 95% CI: 1.151-1.354, p < 0.0001) were associated with the presence of AD. In total participants, the plasma adiponectin level was negatively correlated with MMSE scores (p < 0.0001) and was positively with CDR scores (p < 0.0001) and age (p < 0.0001). The plasma level of leptin was negatively correlated with CDR scores (p < 0.0001) and positively correlated with MMSE scores (p < 0.0001). Both adiponectin (p < 0. 0001) and leptin (p < 0. 0001) featured higher AUC than the random chance. CONCLUSIONS Plasma adiponectin and leptin were associated with the presence, symptomatic severity, and diagnostic power of AD, suggesting a potential role of adipokines in the pathogenesis of AD.
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Affiliation(s)
- Cheng-Chun Liu
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Qing-Hua Wang
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Jia-Yan Xin
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Yu-Hao Liu
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Fan Zeng
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Dong-Wan Chen
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Hui-Yun Li
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Xu Yi
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Gui-Hua Zeng
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Yan-Jiang Wang
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
| | - Yang Xiang
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
- Department of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yang Chen
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
- Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China
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23
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Al-Lahham R, Mendez N. Tau Loss of Function, by Deletion or Aggregation, Contributes to Peripheral Insulin Resistance. J Alzheimers Dis 2023; 95:1041-1058. [PMID: 37638441 PMCID: PMC10578286 DOI: 10.3233/jad-230392] [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] [Accepted: 07/12/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND Several epidemiological data revealed an association between Alzheimer's disease (AD) and type 2 diabetes. Researchers concentrated on brain insulin resistance with little emphasis on the link between systemic insulin resistance and AD, despite the fact that the incidence of type 2 diabetes is higher in AD patients and that impairment in insulin signaling is a risk factor for AD. OBJECTIVE The goal of this study is to determine the role of systemic insulin resistance in the pathogenesis of Alzheimer's disease by evaluating the consequences of tau loss-of-function on peripheral insulin sensitivity. METHODS Primary hepatocytes isolated from transgenic mouse models (Tau KO, P301 L) and wild type mice (C57BL/6) were evaluated for their insulin sensitivity using glucose uptake assays as well as biochemical analysis of insulin signaling markers. RESULTS Our data show that tau deletion or loss of function promotes peripheral insulin resistance as seen in primary hepatocytes isolated from Tau KO and P301 L mice, respectively. Furthermore, exposure of wild-type primary hepatocytes to sub-toxic concentrations of tau oligomers results in a dose-dependent inhibition of glucose uptake, associated with downregulation of insulin signaling. Tau oligomers-induced inactivation of insulin signaling proteins was rescued by inhibition of p38 MAPK, suggesting the involvement of p38 MAPK. CONCLUSIONS This is the first study testing tau role in peripheral insulin resistance at the cellular level using multiple transgenic mouse models. Moreover, this study suggests that tau should be functional for insulin sensitivity, therefore, any loss of function by deletion or aggregation would result in insulin resistance.
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Affiliation(s)
- Rabab Al-Lahham
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Nicolas Mendez
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
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24
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Chen SD, Chuang YC, Lin TK, Yang JL. Alternative role of glucagon-like Peptide-1 receptor agonists in neurodegenerative diseases. Eur J Pharmacol 2022; 938:175439. [PMID: 36470445 DOI: 10.1016/j.ejphar.2022.175439] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 11/02/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022]
Abstract
Aging is a crucial risk factor for common neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Limited options are available for the treatment of age-related, multiple pathogenic mechanism-contributed diseases that usually advance to irreversible conditions with severe neurological deficits and result in a heavy socioeconomic burden on patients, families, and society. A therapy that decelerates disease progression and reduces the socioeconomic burden stemming from these diseases is required. Glucagon-like peptide-1 receptor (GLP-1R) is an important class of medication for type 2 diabetes mellitus (T2DM). Through pancreatic effects, GLP-1R agonists can stimulate insulin secretion, increase β-cell proliferation, reduce β-cell apoptosis, and inhibit glucagon secretion in patients with T2DM. Currently, seven clinically approved GLP-1R agonists are used for T2DM: exenatide, liraglutide, lixisenatide, extended-release exenatide, albiglutide, dulaglutide, and semaglutide. Besides the pancreas, GLP-1Rs are also expressed in organs, such as the gastrointestinal tract, heart, lung, kidney, and brain, indicating their potential use in diseases other than T2DM. Emerging evidence reveals that GLP-1R agonists possess pleiotropic effects that enrich neurogenesis, diminish apoptosis, preclude neurons from oxidative stress, and reduce neuroinflammation in various neurological conditions. These favorable effects may also be employed in neurodegenerative diseases. Herein, we reviewed the recent progress, both in preclinical studies and clinical trials, regarding these clinically used GLP-1R agonists in aging-related neurodegenerative diseases, mainly AD and PD. We stress the pleiotropic characteristics of GLP-1R agonists as repurposing drugs to target multiple pathological mechanisms and for use in the future for these devastating neurodegenerative conditions.
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Affiliation(s)
- Shang-Der Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan; Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan.
| | - Yao-Chung Chuang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan; Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan; College of Medicine, Chang Gung University, Taoyuan City, 33302, Taiwan; Department of Neurology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, 80708, Taiwan.
| | - Tsu-Kung Lin
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan; College of Medicine, Chang Gung University, Taoyuan City, 33302, Taiwan; Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan.
| | - Jenq-Lin Yang
- Institute for Translation Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, 83301, Taiwan.
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25
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Al-Onaizi M, Al-Sarraf A, Braysh K, Kazem F, Al-Hussaini H, Rao M, Kilarkaje N, ElAli A. Impaired spatial navigation and age-dependent hippocampal synaptic dysfunction are associated with chronic inflammatory response in db/db mice. Eur J Neurosci 2022; 56:6003-6021. [PMID: 36226387 DOI: 10.1111/ejn.15835] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 08/18/2022] [Accepted: 09/23/2022] [Indexed: 12/29/2022]
Abstract
Type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease (AD), which has been proposed to be driven by an abnormal neuroinflammatory response affecting cognitive function. However, the impact of T2DM on hippocampal function and synaptic integrity during aging has not been investigated. Here, we investigated the effects of aging in T2DM on AD-like pathology using the leptin receptor-deficient db/db mouse model of T2DM. Our results indicate that adult T2DM mice exhibited impaired spatial acquisition in the Morris water maze (MWM). Morphological analysis showed an age-dependent neuronal loss in the dentate gyrus. We found that astrocyte density was significantly decreased in all regions of the hippocampus in T2DM mice. Our analysis showed that microglial activation was increased in the CA3 and the dentate gyrus of the hippocampus in an age-dependent manner in T2DM mice. However, the expression of presynaptic marker protein (synaptophysin) and the postsynaptic marker protein [postsynaptic density protein 95 (PSD95)] was unchanged in the hippocampus of adult T2DM mice. Interestingly, synaptophysin and PSD95 expression significantly decreased in the hippocampus of aged T2DM mice, suggesting an impaired hippocampal synaptic integrity. Cytokine profiling analysis displayed a robust pro-inflammatory cytokine profile in the hippocampus of aged T2DM mice compared with the younger cohort, outlining the role of aging in exacerbating the neuroinflammatory profile in the diabetic state. Our results suggest that T2DM impairs cognitive function by promoting neuronal loss in the dentate gyrus and triggering an age-dependent deterioration in hippocampal synaptic integrity, associated with an aberrant neuroinflammatory response.
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Affiliation(s)
- Mohammed Al-Onaizi
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Ahmad Al-Sarraf
- Undergraduate Medical Degree Program, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Kawthar Braysh
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Fatema Kazem
- Undergraduate Medical Degree Program, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Heba Al-Hussaini
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Muddanna Rao
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Narayana Kilarkaje
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Ayman ElAli
- Neuroscience Axis, Research Center of CHU de Québec, Université Laval, Quebec City, Quebec, Canada.,Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada
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26
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Cummings J, Ortiz A, Castellino J, Kinney J. Diabetes: Risk factor and translational therapeutic implications for Alzheimer's disease. Eur J Neurosci 2022; 56:5727-5757. [PMID: 35128745 PMCID: PMC9393901 DOI: 10.1111/ejn.15619] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 01/25/2022] [Accepted: 01/27/2022] [Indexed: 12/31/2022]
Abstract
Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) commonly co-occur. T2DM increases the risk for AD by approximately twofold. Animal models provide one means of interrogating the relationship of T2DM to AD and investigating brain insulin resistance in the pathophysiology of AD. Animal models show that persistent hyperglycaemia results in chronic low-grade inflammation that may contribute to the development of neuroinflammation and accelerate the pathobiology of AD. Epidemiological studies suggest that patients with T2DM who received treatment with specific anti-diabetic agents have a decreased risk for the occurrence of AD and all-cause dementia. Agents such as metformin ameliorate T2DM and may have other important systemic effects that lower the risk of AD. Glucagon-like peptide 1 (GLP-1) agonists have been associated with a decreased risk for AD in patients with T2DM. Both insulin and non-insulin anti-diabetic treatments have been evaluated for the treatment of AD in clinical trials. In most cases, patients included in the trials have clinical features of AD but do not have T2DM. Many of the trials were conducted prior to the use of diagnostic biomarkers for AD. Trials have had a wide range of durations and population sizes. Many of the agents used to treat T2DM do not cross the blood brain barrier, and the effects are posited to occur via lowering of peripheral hyperglycaemia and reduction of peripheral and central inflammation. Clinical trials of anti-diabetic agents to treat AD are ongoing and will provide insight into the therapeutic utility of these agents.
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Affiliation(s)
- Jeffrey Cummings
- Chambers‐Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health SciencesUniversity of Nevada Las Vegas (UNLV)Las VegasNevadaUSA
| | - Andrew Ortiz
- Department of Brain Health, School of Integrated Health SciencesUniversity of Nevada Las Vegas (UNLV)Las VegasNevadaUSA
| | | | - Jefferson Kinney
- Chambers‐Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health SciencesUniversity of Nevada Las Vegas (UNLV)Las VegasNevadaUSA,Department of Brain Health, School of Integrated Health SciencesUniversity of Nevada Las Vegas (UNLV)Las VegasNevadaUSA
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27
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Abstract
To maintain energy supply to the brain, a direct energy source called adenosine triphosphate (ATP) is produced by oxidative phosphorylation and aerobic glycolysis of glucose in the mitochondria and cytoplasm. Brain glucose metabolism is reduced in many neurodegenerative diseases, including Alzheimer's disease (AD), where it appears presymptomatically in a progressive and region-specific manner. Following dysregulation of energy metabolism in AD, many cellular repair/regenerative processes are activated to conserve the energy required for cell viability. Glucose metabolism plays an important role in the pathology of AD and is closely associated with the tricarboxylic acid cycle, type 2 diabetes mellitus, and insulin resistance. The glucose intake in neurons is from endothelial cells, astrocytes, and microglia. Damage to neurocentric glucose also damages the energy transport systems in AD. Gut microbiota is necessary to modulate bidirectional communication between the gastrointestinal tract and brain. Gut microbiota may influence the process of AD by regulating the immune system and maintaining the integrity of the intestinal barrier. Furthermore, some therapeutic strategies have shown promising therapeutic effects in the treatment of AD at different stages, including the use of antidiabetic drugs, rescuing mitochondrial dysfunction, and epigenetic and dietary intervention. This review discusses the underlying mechanisms of alterations in energy metabolism in AD and provides potential therapeutic strategies in the treatment of AD.
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28
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Rody T, De Amorim JA, De Felice FG. The emerging neuroprotective roles of exerkines in Alzheimer’s disease. Front Aging Neurosci 2022; 14:965190. [PMID: 36118704 PMCID: PMC9472554 DOI: 10.3389/fnagi.2022.965190] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/11/2022] [Indexed: 11/26/2022] Open
Abstract
Despite the extensive knowledge of the beneficial effects of physical exercise, a sedentary lifestyle is still a predominant harm in our society. Sedentarism is one of the major modifiable risk factors for metabolic diseases such as diabetes mellitus, obesity and neurological disorders, including Alzheimer’s disease (AD)–characterized by synaptic failure, amyloid protein deposition and memory loss. Physical exercise promotes neuroprotective effects through molecules released in circulation and mediates the physiological crosstalk between the periphery and the brain. This literature review summarizes the current understanding of the roles of exerkines, molecules released during physical exercise, as systemic and central factors that mediate the beneficial effects of physical exercise on cognition. We highlight the neuroprotective role of irisin—a myokine released from the proteolytic cleavage of fibronectin type III domain-containing protein 5 (FNDC5) transmembrane protein. Lastly, we review evidence pointing to physical exercise as a potential preventative and interventional strategy against cognitive decline in AD.
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Affiliation(s)
- Tayna Rody
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Julia A. De Amorim
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda G. De Felice
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
- Department of Psychiatry, Queen’s University, Kingston, ON, Canada
- D’Or Institute for Research and Education, Rio de Janeiro, Brazil
- *Correspondence: Fernanda G. De Felice,
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29
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Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases. Int J Mol Sci 2022; 23:ijms23179583. [PMID: 36076972 PMCID: PMC9455625 DOI: 10.3390/ijms23179583] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/17/2022] [Accepted: 08/21/2022] [Indexed: 11/16/2022] Open
Abstract
The glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone well known for its incretin effect in the glucose-dependent stimulation of insulin secretion. However, GLP-1 is also produced in the brain and displays a critical role in neuroprotection and inflammation by activating the GLP-1 receptor signaling pathways. Several studies in vivo and in vitro using preclinical models of neurodegenerative diseases show that GLP-1R activation has anti-inflammatory properties. This review explores the molecular mechanistic action of GLP-1 RAS in relation to inflammation in the brain. These findings update our knowledge of the potential benefits of GLP-1RAS actions in reducing the inflammatory response. These molecules emerge as a potential therapeutic tool in treating neurodegenerative diseases and neuroinflammatory pathologies.
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30
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Luz PLD, Laurindo FRM. Translational Medicine and Implementation Science: How to Transform What We Know Into What We Do. Arq Bras Cardiol 2022; 119:342-345. [PMID: 35946696 PMCID: PMC9363070 DOI: 10.36660/abc.20211029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/09/2022] [Indexed: 11/18/2022] Open
Affiliation(s)
- Protásio Lemos da Luz
- Instituto do Coração (InCor) da Faculdade de Medicina da Universidade de São Paulo HC-FMUSP, São Paulo, SP - Brasil
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31
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Taubel J, Nelson NR, Bansal A, Curran GL, Wang L, Wang Z, Berg HM, Vernon CJ, Min HK, Larson NB, DeGrado TR, Kandimalla KK, Lowe VJ, Pandey MK. Design, Synthesis, and Preliminary Evaluation of [ 68Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer's Disease Mouse Model. Bioconjug Chem 2022; 33:892-906. [PMID: 35420782 PMCID: PMC9121347 DOI: 10.1021/acs.bioconjchem.2c00126] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Aberrant insulin signaling has been considered one of the risk factors for the development of Alzheimer's disease (AD) and has drawn considerable attention from the research community to further study its role in AD pathophysiology. Herein, we describe the development of an insulin-based novel positron emission tomography (PET) probe, [68Ga]Ga-NOTA-insulin, to noninvasively study the role of insulin in AD. The developed PET probe [68Ga]Ga-NOTA-insulin showed a significantly higher uptake (0.396 ± 0.055 SUV) in the AD mouse brain compared to the normal (0.140 ± 0.027 SUV) mouse brain at 5 min post injection and also showed a similar trend at 10, 15, and 20 min post injection. In addition, [68Ga]Ga-NOTA-insulin was found to have a differential uptake in various brain regions at 30 min post injection. Among the brain regions, the cortex, thalamus, brain stem, and cerebellum showed a significantly higher standard uptake value (SUV) of [68Ga]Ga-NOTA-insulin in AD mice as compared to normal mice. The inhibition of the insulin receptor (IR) with an insulin receptor antagonist peptide (S961) in normal mice showed a similar brain uptake profile of [68Ga]Ga-NOTA-insulin as it was observed in the AD case, suggesting nonfunctional IR in AD and the presence of an alternative insulin uptake route in the absence of a functional IR. The Gjedde-Patlak graphical analysis was also performed to predict the input rate of [68Ga]Ga-NOTA-insulin into the brain using MicroPET imaging data and supported the in vivo results. The [68Ga]Ga-NOTA-insulin PET probe was successfully synthesized and evaluated in a mouse model of AD in comparison with [18F]AV1451 and [11C]PIB to noninvasively study the role of insulin in AD pathophysiology.
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Affiliation(s)
- Jillissa
C. Taubel
- Division
of Nuclear Medicine, Department of Radiology, Mayo Clinic Rochester, Minnesota 55905, United States
| | - Nicholas R. Nelson
- Division
of Nuclear Medicine, Department of Radiology, Mayo Clinic Rochester, Minnesota 55905, United States
| | - Aditya Bansal
- Division
of Nuclear Medicine, Department of Radiology, Mayo Clinic Rochester, Minnesota 55905, United States
| | - Geoffrey L. Curran
- Division
of Nuclear Medicine, Department of Radiology, Mayo Clinic Rochester, Minnesota 55905, United States
| | - Lushan Wang
- Department
of Pharmaceutics, College of Pharmacy, University
of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Zengtao Wang
- Department
of Pharmaceutics, College of Pharmacy, University
of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Heather M. Berg
- Division
of Nuclear Medicine, Department of Radiology, Mayo Clinic Rochester, Minnesota 55905, United States
| | - Cynthia J. Vernon
- Division
of Nuclear Medicine, Department of Radiology, Mayo Clinic Rochester, Minnesota 55905, United States
| | - Hoon-Ki Min
- Division
of Nuclear Medicine, Department of Radiology, Mayo Clinic Rochester, Minnesota 55905, United States
| | - Nicholas B. Larson
- Department
of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota 55905, United States
| | - Timothy R. DeGrado
- Department
of Radiology, University of Colorado Anschutz
Medical Campus, Aurora, Colorado 80045, United States
| | - Karunya K. Kandimalla
- Department
of Pharmaceutics, College of Pharmacy, University
of Minnesota, Minneapolis, Minnesota 55455, United States,
| | - Val J. Lowe
- Division
of Nuclear Medicine, Department of Radiology, Mayo Clinic Rochester, Minnesota 55905, United States,
| | - Mukesh K. Pandey
- Division
of Nuclear Medicine, Department of Radiology, Mayo Clinic Rochester, Minnesota 55905, United States,
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32
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Cimini FA, Perluigi M, Barchetta I, Cavallo MG, Barone E. Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update. Int J Mol Sci 2022; 23:5574. [PMID: 35628384 PMCID: PMC9141761 DOI: 10.3390/ijms23105574] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/13/2022] [Accepted: 05/14/2022] [Indexed: 11/16/2022] Open
Abstract
Insulin signaling is a conserved pathway that orchestrates glucose and lipid metabolism, energy balance, and inflammation, and its dysregulation compromises the homeostasis of multiple systems. Insulin resistance is a shared hallmark of several metabolic diseases, including obesity, metabolic syndrome, and type 2 diabetes, and has been associated with cognitive decline during aging and dementia. Numerous mechanisms promoting the development of peripheral and central insulin resistance have been described, although most of them were not completely clarified. In the last decades, several studies have highlighted that biliverdin reductase-A (BVR-A), over its canonical role in the degradation of heme, acts as a regulator of insulin signaling. Evidence from human and animal studies show that BVR-A alterations are associated with the aberrant activation of insulin signaling, metabolic syndrome, liver steatosis, and visceral adipose tissue inflammation in obese and diabetic individuals. In addition, recent findings demonstrated that reduced BVR-A levels or impaired BVR-A activation contribute to the development of brain insulin resistance and metabolic alterations in Alzheimer's disease. In this narrative review, we will provide an overview on the literature by focusing on the role of BVR-A in the regulation of insulin signaling and how BVR-A alterations impact on cell dysfunctions in both metabolic and neurodegenerative disorders.
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Affiliation(s)
- Flavia Agata Cimini
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy; (F.A.C.); (I.B.)
| | - Marzia Perluigi
- Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, 00185 Rome, Italy; (M.P.); (E.B.)
| | - Ilaria Barchetta
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy; (F.A.C.); (I.B.)
| | - Maria Gisella Cavallo
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy; (F.A.C.); (I.B.)
| | - Eugenio Barone
- Department of Biochemical Sciences “A. Rossi-Fanelli”, Sapienza University of Rome, 00185 Rome, Italy; (M.P.); (E.B.)
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Yang JJ. Brain insulin resistance and the therapeutic value of insulin and insulin-sensitizing drugs in Alzheimer's disease neuropathology. Acta Neurol Belg 2022; 122:1135-1142. [PMID: 35482277 DOI: 10.1007/s13760-022-01907-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023]
Abstract
The incidence of Alzheimer's disease (AD) is significantly higher in people with diabetes. Insulin and insulin receptor (IR) signaling intermediates are expressed in the brain. Insulin exerts multiple function in the brain. The role of compromised IR signaling in AD pathogenesis and the therapeutic value of insulin attract broad attention. This review summarizes the collective insulin action in the brain related to key factors of AD pathogenesis, updates the key features of insulin resistance in the AD brain and assesses the therapeutic potential of insulin and insulin-sensitizing drugs. Insulin stimulates neural growth and survival, suppresses amyloidogenic processing of the amyloid precursor protein (AβPP) and inhibits the Tau phosphorylation kinase, glycogen synthase kinase 3β. Central nervous IR signaling regulates systemic metabolism and increases glucose availability to neurons. The expression of IR and its downstream effectors is reduced in AD brain tissues. Insulin and insulin-sensitizing drugs can improve cognitive function in AD patients and AD animal models. Systemic insulin delivery is less effective than intranasal insulin treatment. The penetrance of insulin-sensitizing drugs to the blood brain barrier is problematic and new brain-prone drugs need be developed. Insulin resistance manifested by the degradation and the altered phosphorylation of IR intermediates precedes overt AD syndrome. Type 3 diabetes as a pure form of brain insulin resistance without systemic insulin resistance is proposed as a causal factor in AD. Further research is needed for the identification of critical factors leading to impaired IR signaling and the development of new molecules to stimulate brain IR signaling.
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Affiliation(s)
- James J Yang
- Marriotts Ridge High School, 12100 Woodford Dr, Marriottsville, MD, 21104, USA.
- , 3060 Seneca Chief Trail, Ellicott City, MD, 21042, USA.
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Chronic exposure of bisphenol-A impairs cognitive function and disrupts hippocampal insulin signaling pathway in male mice. Toxicology 2022; 472:153192. [PMID: 35489422 DOI: 10.1016/j.tox.2022.153192] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 04/23/2022] [Accepted: 04/25/2022] [Indexed: 01/04/2023]
Abstract
Bisphenol-A (BPA), a well-known estrogenic endocrine disruptor, is generally applied to turn out plastic consumer products. Available data have manifested that exposure to BPA can trigger insulin resistance. Hence, the purpose of the actual study was to consider the impacts of BPA exposure on cognitive function and insulin signaling pathway in the hippocampus of male offspring mice. For this purpose, the pregnant female mice were treated either vehicle (0.1% ethanol) or BPA (0.01, 0.1, and 1µg/mL) via drinking water from day 1 of gestation until delactation (D1-PND21, newborn exposure). Afterward, the three-week-old male offspring mice took orally with the same doses of BPA for nine weeks (PND84). The behavioral tests, blood sugar level, histological observation, transcriptome sequencing, glucose transporter 4 (GLUT4), and hippocampal insulin signaling pathway were checked for the male offspring mice at 13 weeks of age (PND91). Our data indicated that BPA exposure impaired cognitive function, disrupted the hippocampal regular cell arrangement, increased blood glucose levels, disturbed the insulin signaling pathway including phosphorylated insulin receptor substrate1 (p-IRS1), protein kinase B (p-AKT), and glycogen synthase kinase 3β (p-GSK3β). At the same time, the mRNA and protein expressions of GLUT4 were markedly down-regulated in the BPA-exposed groups. To sum up, it has been suggested from these results that BPA has detrimental effects on the insulin signaling pathway, which might subsequently be conducive to the impairment of cognitive function in the adult male offspring mice. Therefore, BPA exposure might in part be an element of risk for the long-term neurodegeneration in male offspring mice.
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Sun M, Wang L, Guo Y, Yan S, Li J, Wang X, Li X, Li B. The Association Among Inflammatory Diet, Glycohemoglobin, and Cognitive Function Impairment in the Elderly: Based on the NHANES 2011–2014. J Alzheimers Dis 2022; 87:1713-1723. [DOI: 10.3233/jad-215688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: Dietary inflammatory index (DII) was associated with Type 2 diabetes mellitus and cognitive function impairment (CFI). Objective: The aim of this study was to explore whether the associations among DII, glycohemoglobin (HbA1c), and CFI were similar in the participants with or without diabetes. Methods: A total of 1,198 participants aged 60 and over from the National Health and Nutrition Examination Survey (NHANES) in 2011–2014 were involved in this study, dividing into subgroups as diabetes and non-diabetes for further analysis. Results: We found that participants with pro-inflammatory diet had higher proportion of CFI patients (p < 0.05). Pro-inflammatory diet and HbA1c were positively associated with the risk of CFI; participants with pro-inflammatory diet was 1.479 times on occurrence of CFI compared with anti-inflammatory diet group. The interaction between inflammatory diet and HbA1c was positive on the risk of CFI and was negative on the CERAD-immediate and CERAD-delayed, respectively. Among the participants without diabetes, the associations of Energy-adjusted DII (E-DII) with Animal Fluency test and Digit Symbol Substitution Test (DSST) were partially mediated by HbA1c, and the mediated proportion was 5.8% and 6.6%, respectively. However, there was no such mediation effect in the diabetes patients. Conclusion: In elderly participants without diabetes, there was an interaction between inflammatory diet and HbA1c on the association with CFI, especially for the dimension of CERAD-immediate and CERAD-delayed. Besides, the associations of E-DII with Animal Fluency test and DSST were partially mediated by HbA1c. For diabetic patients, HbA1c, rather than the inflammatory diet has a positive effect on the CFI risk.
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Affiliation(s)
- Mengzi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, P. R. China
| | - Ling Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, P. R. China
| | - Yinpei Guo
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, P. R. China
| | - Shoumeng Yan
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, P. R. China
| | - Jing Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, P. R. China
| | - Xuhan Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, P. R. China
| | - Xiaotong Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, P. R. China
| | - Bo Li
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, P. R. China
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Lanz M, Janeiro MH, Milagro FI, Puerta E, Ludwig IA, Pineda-Lucena A, Ramírez MJ, Solas M. Trimethylamine N-Oxide (TMAO) drives insulin resistance and cognitive deficiencies in a senescence accelerated mouse model. Mech Ageing Dev 2022; 204:111668. [PMID: 35341897 DOI: 10.1016/j.mad.2022.111668] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/09/2022] [Accepted: 03/22/2022] [Indexed: 12/20/2022]
Abstract
It has been established that ageing is the major risk factor for cognitive deficiency and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. In the present study, peripheral and central insulin resistance was found in SAMP8 mice (aging mouse model) accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state was observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across an aging-disrupted blood brain barrier. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment that decreases TMAO levels. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between aging, insulin resistance and dementia. Thus, pharmacological intervention that leads to decreased TMAO levels, such as DMB, could open a new avenue for the future treatment of neurodegenerative diseases.
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Affiliation(s)
- María Lanz
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain
| | - Manuel H Janeiro
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain; IdISNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Fermin I Milagro
- IdISNA, Navarra Institute for Health Research, Pamplona, Spain; Department of Nutrition, Food Science and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain; CIBERobn, CIBER Fisiopatología de Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Elena Puerta
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain; IdISNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Iziar A Ludwig
- Program of Molecular Therapeutics, Center for Applied Medical Research (CIMA), Universidad de Navarra, Avda. Pío XII 55, E-31008 Pamplona, Spain
| | - Antonio Pineda-Lucena
- Program of Molecular Therapeutics, Center for Applied Medical Research (CIMA), Universidad de Navarra, Avda. Pío XII 55, E-31008 Pamplona, Spain
| | - María J Ramírez
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain; IdISNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Maite Solas
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain; IdISNA, Navarra Institute for Health Research, Pamplona, Spain.
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De Felice FG, Gonçalves RA, Ferreira ST. Impaired insulin signalling and allostatic load in Alzheimer disease. Nat Rev Neurosci 2022; 23:215-230. [PMID: 35228741 DOI: 10.1038/s41583-022-00558-9] [Citation(s) in RCA: 116] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2022] [Indexed: 12/14/2022]
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Confettura AD, Cuboni E, Ammar MR, Jia S, Gomes GM, Yuanxiang P, Raman R, Li T, Grochowska KM, Ahrends R, Karpova A, Dityatev A, Kreutz MR. Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer's disease. Transl Neurodegener 2022; 11:2. [PMID: 34986876 PMCID: PMC8734066 DOI: 10.1186/s40035-021-00277-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/24/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer's disease. It has been proposed that neuroinflammation might be an intervening variable, but the underlying mechanisms are currently unknown. METHODS We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load, neuroinflammation, and diet-induced obesity to test hypotheses on underlying mechanisms. RESULTS We found that neddylation and subsequent activation of cullin-RING ligase complexes induced synaptic insulin resistance through ubiquitylation and degradation of the insulin-receptor substrate IRS1 that organizes synaptic insulin signaling. Accordingly, inhibition of neddylation preserved synaptic insulin signaling and rescued memory deficits in mice with a high amyloid load, which were fed with a 'western diet'. CONCLUSIONS Collectively, the data suggest that neddylation and degradation of the insulin-receptor substrate is a nodal point that links high amyloid load, neuroinflammation, and synaptic insulin resistance to cognitive decline and impaired synaptic plasticity in high-risk aging.
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Affiliation(s)
| | - Eleonora Cuboni
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany
| | - Mohamed Rafeet Ammar
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany
| | - Shaobo Jia
- German Center for Neurodegenerative Diseases (DZNE), 39120, Magdeburg, Germany
| | - Guilherme M Gomes
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Otto Von Guericke University, 39120, Magdeburg, Germany
| | - PingAn Yuanxiang
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany
| | - Rajeev Raman
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany
| | - Tingting Li
- Leibniz-Institut Für Analytische Wissenschaften-ISAS-e.V., 44227, Dortmund, Germany
| | - Katarzyna M Grochowska
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany.,Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
| | - Robert Ahrends
- Leibniz-Institut Für Analytische Wissenschaften-ISAS-e.V., 44227, Dortmund, Germany.,Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090, Wien, Austria
| | - Anna Karpova
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Otto Von Guericke University, 39120, Magdeburg, Germany
| | - Alexander Dityatev
- German Center for Neurodegenerative Diseases (DZNE), 39120, Magdeburg, Germany.,Center for Behavioral Brain Sciences, Otto Von Guericke University, 39120, Magdeburg, Germany.,Medical Faculty, Otto-von-Guericke University, 39120, Magdeburg, Germany
| | - Michael R Kreutz
- RG Neuroplasticity, Leibniz-Institute for Neurobiology, 39118, Magdeburg, Germany. .,German Center for Neurodegenerative Diseases (DZNE), 39120, Magdeburg, Germany. .,Center for Behavioral Brain Sciences, Otto Von Guericke University, 39120, Magdeburg, Germany. .,Leibniz Group 'Dendritic Organelles and Synaptic Function', Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany.
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He K, Nie L, Ali T, Wang S, Chen X, Liu Z, Li W, Zhang K, Xu J, Liu J, Yu Z, Yang X, Li S. Adiponectin alleviated Alzheimer-like pathologies via autophagy-lysosomal activation. Aging Cell 2021; 20:e13514. [PMID: 34775673 PMCID: PMC8672778 DOI: 10.1111/acel.13514] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 12/24/2022] Open
Abstract
Adiponectin (APN) deficiency has also been associated with Alzheimer‐like pathologies. Recent studies have illuminated the importance of APN signaling in reducing Aβ accumulation, and the Aβ elimination mechanism remains rudimentary. Therefore, we aimed to elucidate the APN role in reducing Aβ accumulation and its associated abnormalities by targeting autophagy and lysosomal protein changes. To assess, we performed a combined pharmacological and genetic approach while using preclinical models and human samples. Our results demonstrated that the APN level significantly diminished in the plasma of patients with dementia and 5xFAD mice (6 months old), which positively correlated with Mini‐Mental State Examination (MMSE), and negatively correlated with Clinical Dementia Rating (CDR), respectively. APN deficiency accelerated cognitive impairment, Aβ deposition, and neuroinflammation in 5xFAD mice (5xFAD*APN KO), which was significantly rescued by AdipoRon (AR) treatment. Furthermore, AR treatment also markedly reduced Aβ deposition and attenuated neuroinflammation in APP/PS1 mice without altering APP expression and processing. Interestingly, AR treatment triggered autophagy by mediating AMPK‐mTOR pathway signaling. Most importantly, APN deficiency dysregulated lysosomal enzymes level, which was recovered by AR administration. We further validated these changes by proteomic analysis. These findings reveal that APN is the negative regulator of Aβ deposition and its associated pathophysiologies. To eliminate Aβ both extra‐ and intracellular deposition, APN contributes via the autophagic/lysosomal pathway. It presents a therapeutic avenue for AD therapy by targeting autophagic and lysosomal signaling.
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Affiliation(s)
- Kaiwu He
- State Key Laboratory of Oncogenomics School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Shenzhen China
- Shenzhen Key Laboratory of Modern Toxicology Shenzhen Medical Key Discipline of Health Toxicology Shenzhen Center for Disease Control and Prevention Shenzhen China
| | - Lulin Nie
- Shenzhen Key Laboratory of Modern Toxicology Shenzhen Medical Key Discipline of Health Toxicology Shenzhen Center for Disease Control and Prevention Shenzhen China
| | - Tahir Ali
- State Key Laboratory of Oncogenomics School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Shenzhen China
| | - Shujin Wang
- Department of Neurology the First People’s Hospital of Zibo Affiliated to Weifang Medical College Zibo China
| | - Xiao Chen
- Shenzhen Key Laboratory of Modern Toxicology Shenzhen Medical Key Discipline of Health Toxicology Shenzhen Center for Disease Control and Prevention Shenzhen China
| | - Zizhen Liu
- State Key Laboratory of Oncogenomics School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Shenzhen China
| | - Weifen Li
- State Key Laboratory of Oncogenomics School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Shenzhen China
| | - Kaiqin Zhang
- Shenzhen Key Laboratory of Modern Toxicology Shenzhen Medical Key Discipline of Health Toxicology Shenzhen Center for Disease Control and Prevention Shenzhen China
- College of Public Health University of South China Hengyang China
| | - Jia Xu
- Shenzhen Key Laboratory of Modern Toxicology Shenzhen Medical Key Discipline of Health Toxicology Shenzhen Center for Disease Control and Prevention Shenzhen China
- Department of Pathophysiology Guangzhou Medical University Guangzhou China
| | - Jianjun Liu
- Shenzhen Key Laboratory of Modern Toxicology Shenzhen Medical Key Discipline of Health Toxicology Shenzhen Center for Disease Control and Prevention Shenzhen China
| | - Zhi‐Jian Yu
- Department of Infectious Diseases and Shenzhen key laboratory for endogenous infections the 6th Affiliated Hospital of Shenzhen University Health Science Center Nanshan District Shenzhen China
| | - Xifei Yang
- Shenzhen Key Laboratory of Modern Toxicology Shenzhen Medical Key Discipline of Health Toxicology Shenzhen Center for Disease Control and Prevention Shenzhen China
| | - Shupeng Li
- State Key Laboratory of Oncogenomics School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Shenzhen China
- Campbell Research Institute Centre for Addiction and Mental Health Toronto Ontario Canada
- Department of Psychiatry University of Toronto Toronto Ontario Canada
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Ikeda Y, Nagase N, Tsuji A, Kitagishi Y, Matsuda S. Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer’s disease. World J Biol Chem 2021; 12:104-113. [PMID: 34904048 PMCID: PMC8637616 DOI: 10.4331/wjbc.v12.i6.104] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/21/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
Alzheimer’s disease (AD) is the most common reason for progressive dementia in the elderly. It has been shown that disorders of the mammalian/mechanistic target of rapamycin (mTOR) signaling pathways are related to the AD. On the other hand, diabetes mellitus (DM) is a risk factor for the cognitive dysfunction. The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate, which contains neuro-inflammation and/or neurodegeneration and dementia. Glucagon-like peptide-1 (GLP1) is interesting as a possible link between metabolism and brain impairment. Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD. The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit. They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes. Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4 (DPP4) inhibitors, being currently used for DM therapy, may also be effective for AD treatment. The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models. Although further studies for mTOR, GLP1, and DPP4 signaling pathways in humans would be intensively required, they seem to be a promising approach for innovative AD-treatments. We would like to review the characteristics of AD pathogenesis, the key roles of mTOR in AD and the preventive and/ or therapeutic suggestions of directing the mTOR signaling pathway.
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Affiliation(s)
- Yuka Ikeda
- Food Science and Nutrition, Nara Women’s University, Nara 630-8506, Japan
| | - Nozomi Nagase
- Food Science and Nutrition, Nara Women’s University, Nara 630-8506, Japan
| | - Ai Tsuji
- Food Science and Nutrition, Nara Women’s University, Nara 630-8506, Japan
| | - Yasuko Kitagishi
- Food Science and Nutrition, Nara Women’s University, Nara 630-8506, Japan
| | - Satoru Matsuda
- Food Science and Nutrition, Nara Women’s University, Nara 630-8506, Japan
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Barone E, Di Domenico F, Perluigi M, Butterfield DA. The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease. Free Radic Biol Med 2021; 176:16-33. [PMID: 34530075 PMCID: PMC8595768 DOI: 10.1016/j.freeradbiomed.2021.09.006] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/31/2021] [Accepted: 09/09/2021] [Indexed: 02/08/2023]
Abstract
Alzheimer's disease (AD) is the most common form of dementia in the elderly followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia and insulin resistance, as a risk factor for AD and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported in recent clinical and preclinical studies. Brain functions require continuous supply of glucose and oxygen and a tight regulation of metabolic processes. Loss of this metabolic regulation has been proposed to be a contributor to memory dysfunction associated with neurodegeneration. Within the above scenario, this review will focus on the interplay among oxidative stress (OS), insulin resistance and AMPK dysfunctions in the brain by highlighting how these neurotoxic events contribute to neurodegeneration. We provide an overview on the detrimental effects of OS on proteins regulating insulin signaling and how these alterations impact cell metabolic dysfunctions through AMPK dysregulation. Such processes, we assert, are critically involved in the molecular pathways that underlie AD.
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Affiliation(s)
- Eugenio Barone
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy
| | - Fabio Di Domenico
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy
| | - Marzia Perluigi
- Department of Biochemical Sciences "A. Rossi-Fanelli", Sapienza University of Rome, Piazzale A. Moro 5, 00185, Roma, Italy
| | - D Allan Butterfield
- Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40506-0055, USA.
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Behl T, Arora A, Sehgal A, Singh S, Sharma N, Bhatia S, Al-Harrasi A, Bungau S, Mostafavi E. Molecular and Biochemical Pathways Encompassing Diabetes Mellitus and Dementia. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 21:542-556. [PMID: 34758720 DOI: 10.2174/1871527320666211110115257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/25/2021] [Accepted: 09/15/2021] [Indexed: 11/22/2022]
Abstract
Diabetes mellitus is a major metabolic disorder that has now emerged as an epidemic, and it affects the brain through an array of pathways. Diabetes mellitus patients can develop pathological changes in the brain, which eventually take the shape of mild cognitive impairment progressing to Alzheimer's Disease. A number of preclinical and clinical studies demonstrate this fact, and it comes out to be those molecular pathways such as amyloidogenesis, oxidative stress, inflammation, and impaired insulin signaling are identical in diabetes mellitus and dementia. However, the critical player involved in the vicious cycle of diabetes mellitus and dementia is insulin, whose signaling, when impaired in diabetes mellitus (both type 1 and 2), leads to a decline in cognition, although other pathways are also essential contributors. Moreover, it is not only that diabetes mellitus patients indicate cognitive decline at a later stage; many Alzheimer's Disease patients also reflect symptoms of diabetes mellitus, thus creating a vicious cycle inculcating a web of complex molecular mechanisms and hence categorizing Alzheimer's Disease as 'brain diabetes'. Thus, it is practical to suggest that anti-diabetic drugs are beneficial in Alzheimer's Disease; but only smaller trials, not the larger ones, have showcased positive outcomes mainly because of the late onset of therapy. Therefore, it is extremely important to develop more of such molecules that target insulin in dementia patients along with such methods that diagnose impaired insulin signaling and the associated cognitive decline so that early therapy may be initiated and the progression of the disease be prevented.
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Affiliation(s)
- Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Arpita Arora
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab. India
| | - Saurabh Bhatia
- Amity Institute of Pharmacy, Amity University, Haryana. India
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa. Oman
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea. Romania
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA. United States
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Diabetes and Alzheimer's Disease: Might Mitochondrial Dysfunction Help Deciphering the Common Path? Antioxidants (Basel) 2021; 10:antiox10081257. [PMID: 34439505 PMCID: PMC8389322 DOI: 10.3390/antiox10081257] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
A growing number of clinical and epidemiological studies support the hypothesis of a tight correlation between type 2 diabetes mellitus (T2DM) and the development risk of Alzheimer's disease (AD). Indeed, the proposed definition of Alzheimer's disease as type 3 diabetes (T3D) underlines the key role played by deranged insulin signaling to accumulation of aggregated amyloid beta (Aβ) peptides in the senile plaques of the brain. Metabolic disturbances such as hyperglycemia, peripheral hyperinsulinemia, dysregulated lipid metabolism, and chronic inflammation associated with T2DM are responsible for an inefficient transport of insulin to the brain, producing a neuronal insulin resistance that triggers an enhanced production and deposition of Aβ and concomitantly contributes to impairment in the micro-tubule-associated protein Tau, leading to neural degeneration and cognitive decline. Furthermore, the reduced antioxidant capacity observed in T2DM patients, together with the impairment of cerebral glucose metabolism and the decreased performance of mitochondrial activity, suggests the existence of a relationship between oxidative damage, mitochondrial impairment, and cognitive dysfunction that could further reinforce the common pathophysiology of T2DM and AD. In this review, we discuss the molecular mechanisms by which insulin-signaling dysregulation in T2DM can contribute to the pathogenesis and progression of AD, deepening the analysis of complex mechanisms involved in reactive oxygen species (ROS) production under oxidative stress and their possible influence in AD and T2DM. In addition, the role of current therapies as tools for prevention or treatment of damage induced by oxidative stress in T2DM and AD will be debated.
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Scherer T, Sakamoto K, Buettner C. Brain insulin signalling in metabolic homeostasis and disease. Nat Rev Endocrinol 2021; 17:468-483. [PMID: 34108679 DOI: 10.1038/s41574-021-00498-x] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 02/06/2023]
Abstract
Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.
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Affiliation(s)
- Thomas Scherer
- Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Kenichi Sakamoto
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Christoph Buettner
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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Gonçalves RA, De Felice FG. The crosstalk between brain and periphery: Implications for brain health and disease. Neuropharmacology 2021; 197:108728. [PMID: 34331960 DOI: 10.1016/j.neuropharm.2021.108728] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/19/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
Mounting evidence indicates that signaling molecules identified primarily in the peripheral circulation can affect cognitive function in physiological and pathological conditions, including in the development of several neurological diseases. However, considering the properties of the vascular blood-brain barrier (BBB), circulating lipophobic molecules would not be expected to cross this vascular structure. Thus, if and how peripheral lipophobic molecules, such as hormones and cytokines, reach the brain to exert their reported effects remains to be better established. In this review, we will discuss evidence for and against the ability of molecules in the circulation, such as insulin, cytokines, and irisin to reach the brain and mediate the crosstalk between peripheral tissues and the central nervous system (CNS). We hypothesize that in addition to entering the brain via receptor-mediated transcytosis, these circulating molecules can have their transport facilitated by extracellular vesicles or under pathological conditions when the BBB is disrupted. We also discuss the possibility that these circulating molecules access the brain by acting directly on circumventricular organs, which lack the BBB, by local synthesis in the choroid plexus, and via activation of afferent vagal nerves. Advancing the understanding of mechanisms implicated in the transport of blood-borne molecules to the CNS will help us elucidate the contribution of peripheral factors to brain health and disease, and will enable the development of minimally invasive strategies to deliver therapeutic drugs to the brain in neurological disorders.
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Affiliation(s)
- Rafaella A Gonçalves
- Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
| | - Fernanda G De Felice
- Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada; Department of Psychiatry, Queen's University, Kingston, ON K7L 3N6, Canada; D'Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, 22281-100, Brazil; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, 21941-902, Brazil.
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Ettcheto M, Sánchez-Lopez E, Cano A, Carrasco M, Herrera K, Manzine PR, Espinosa-Jimenez T, Busquets O, Verdaguer E, Olloquequi J, Auladell C, Folch J, Camins A. Dexibuprofen ameliorates peripheral and central risk factors associated with Alzheimer's disease in metabolically stressed APPswe/PS1dE9 mice. Cell Biosci 2021; 11:141. [PMID: 34294142 PMCID: PMC8296685 DOI: 10.1186/s13578-021-00646-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/04/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Several studies stablished a relationship between metabolic disturbances and Alzheimer´s disease (AD) where inflammation plays a pivotal role. However, mechanisms involved still remain unclear. In the present study, we aimed to evaluate central and peripheral effects of dexibuprofen (DXI) in the progression of AD in APPswe/PS1dE9 (APP/PS1) female mice, a familial AD model, fed with high fat diet (HFD). Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice, at 6 months. Moreover, mice were divided into subgroups to which were administered drinking water or water supplemented with DXI (20 mg kg-1 d-1) for 3 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-ITT) were performed to evaluate peripheral parameters and also behavioral tests to determine cognitive decline. Moreover, molecular studies such as Western blot and RT-PCR were carried out in liver to confirm metabolic effects and in hippocampus to analyze several pathways considered hallmarks in AD. RESULTS Our studies demonstrate that DXI improved metabolic alterations observed in transgenic animals fed with HFD in vivo, data in accordance with those obtained at molecular level. Moreover, an improvement of cognitive decline and neuroinflammation among other alterations associated with AD were observed such as beta-amyloid plaque accumulation and unfolded protein response. CONCLUSIONS Collectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.
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Affiliation(s)
- Miren Ettcheto
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain.
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain.
- Unitat de Farmacologia I Farmacognòsia, Facultat de Farmàcia I Ciències de L'Alimentació, Universitat de Barcelona, Av. Joan XXIII 27/31, 08028, Barcelona, Spain.
| | - Elena Sánchez-Lopez
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain
- Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain
| | - Amanda Cano
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain
- Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain
- Research Center and Memory Clinic, Fundació ACE. Institut Català de Neurociències Aplicades - International University of Catalunya (UIC), Barcelona, Spain
| | - Marina Carrasco
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
- Department of Biochemistry and Biotechnology, Faculty of Medicine and Life Science, University Rovira I Virgili, Reus, Spain
| | - Katherine Herrera
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
- Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Patricia R Manzine
- Department of Gerontology, Federal University of São Carlos (UFSCar), São Carlos, 13565-905, Brazil
| | - Triana Espinosa-Jimenez
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Oriol Busquets
- Dominick P. Purpura Department of Neurosciences, Albert Einstein College of Medicine, New York City (10461), USA
| | - Ester Verdaguer
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
- Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Jordi Olloquequi
- Laboratory of Cellular and Molecular Pathology, Facultad de Ciencias de La Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Carme Auladell
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
- Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Jaume Folch
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Biochemistry and Biotechnology, Faculty of Medicine and Life Science, University Rovira I Virgili, Reus, Spain
| | - Antoni Camins
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
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Serum Corticosterone and Insulin Resistance as Early Biomarkers in the hAPP23 Overexpressing Mouse Model of Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms22136656. [PMID: 34206322 PMCID: PMC8269119 DOI: 10.3390/ijms22136656] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/16/2021] [Accepted: 06/18/2021] [Indexed: 12/21/2022] Open
Abstract
Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer’s disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/−) AD mouse model. Memory and spatial learning of male hAPP23+/− and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/− brains, amyloid-beta (Aβ) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/− mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/− animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/− mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/− mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD.
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Wu Z, Chen C, Kang SS, Liu X, Gu X, Yu SP, Keene CD, Cheng L, Ye K. Neurotrophic signaling deficiency exacerbates environmental risks for Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A 2021; 118:e2100986118. [PMID: 34140411 PMCID: PMC8237621 DOI: 10.1073/pnas.2100986118] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The molecular mechanism of Alzheimer's disease (AD) pathogenesis remains obscure. Life and/or environmental events, such as traumatic brain injury (TBI), high-fat diet (HFD), and chronic cerebral hypoperfusion (CCH), are proposed exogenous risk factors for AD. BDNF/TrkB, an essential neurotrophic signaling for synaptic plasticity and neuronal survival, are reduced in the aged brain and in AD patients. Here, we show that environmental factors activate C/EBPβ, an inflammatory transcription factor, which subsequently up-regulates δ-secretase that simultaneously cleaves both APP and Tau, triggering AD neuropathological changes. These adverse effects are additively exacerbated in BDNF+/- or TrkB+/- mice. Strikingly, TBI provokes both senile plaque deposit and neurofibrillary tangles (NFT) formation in TrkB+/- mice, associated with augmented neuroinflammation and extensive neuronal loss, leading to cognitive deficits. Depletion of C/EBPβ inhibits TBI-induced AD-like pathologies in these mice. Remarkably, amyloid aggregates and NFT are tempospatially distributed in TrkB+/- mice brains after TBI, providing insight into their spreading in the progression of AD-like pathologies. Hence, our study revealed the roles of exogenous (TBI, HFD, and CCH) and endogenous (TrkB/BDNF) risk factors in the onset of AD-associated pathologies.
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Affiliation(s)
- Zhourui Wu
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, China
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education, Shanghai 200072, China
| | - Chun Chen
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Seong Su Kang
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Xia Liu
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - Xiaohuan Gu
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322
| | - Shan Ping Yu
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322
| | - C Dirk Keene
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104
| | - Liming Cheng
- Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, China;
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education, Shanghai 200072, China
| | - Keqiang Ye
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322;
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Moustafa SR. The immune-opioid axis in prediabetes: predicting prediabetes with insulin resistance by plasma interleukin-10 and endomorphin-2 to kappa-opioid receptors ratio. Diabetol Metab Syndr 2021; 13:61. [PMID: 34099024 PMCID: PMC8185911 DOI: 10.1186/s13098-021-00677-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 05/20/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Prediabetes is characterized by a hemoglobin A1c of 5.7-6.4% and fasting blood glucose of 100-125 mg/dl. A high percentage of prediabetes subjects develop type 2 diabetes mellitus in the next years. The effects of opioid peptides and their receptors, in addition to immunological cytokines, on prediabetes are not well understood. Therefore, molecular, physiological, and clinical studies are required to link the opioid system, immune system, and insulin resistance (IR) in prediabetes. We hypothesize that opioid peptides (endomorphin-2 (EM2), and β-endorphin (βEP)), and their receptors (µ-opioid receptors (MOR) and κ-opioid receptors (KOR)), in addition to the inflammatory cytokines (IL-6) and anti-inflammatory cytokine (IL-10), affect IR parameters in patients with prediabetes. METHODS Sixty prediabetes patients with IR (prediabetes+IR) and sixty prediabetes patients without IR (prediabetes-IR), in addition to 58 controls, have participated in the study. IL-6, IL-10, EM2, βEP, MOR, and KOR were measured by the ELISA technique. RESULTS In general, most prediabetes subjects have dyslipidemia. The IL-6, IL-10, β-endorphin, MOR, and endomorphin-2 were higher in the prediabetes subgroups than the control group. The immune system was activated in the prediabetes in an IR-dependent manner. Prediabetes+IR can be predicted by the increased levels of IL-10, βEP, and EM2 and by the combination of IL-10 and EM2/KOR with good sensitivity and specificity. CONCLUSION Opioid peptides and their receptors were upregulated in patients with prediabetes, depending on the significance of IR and the immune cytokines. The intercorrelation between the immune system, EOS, and insulin in prediabetes was confirmed.
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Affiliation(s)
- Shatha Rouf Moustafa
- Clinical Analysis Department, College of Pharmacy, Hawler Medical University, Roya Towers C21, Erbil, Iraq.
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50
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El Massry M, Alaeddine LM, Ali L, Saad C, Eid AA. Metformin: A Growing Journey from Glycemic Control to the Treatment of Alzheimer's Disease and Depression. Curr Med Chem 2021; 28:2328-2345. [PMID: 32900343 DOI: 10.2174/0929867327666200908114902] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/30/2020] [Accepted: 07/07/2020] [Indexed: 11/22/2022]
Abstract
Metabolic stress, transduced as an altered cellular redox and energy status, presents as the main culprit in many diseases, including diabetes. However, its role in the pathology of neurological disorders is still not fully elucidated. Metformin, a biguanide compound, is an FDA approved antidiabetic drug generally used for the treatment of type 2 diabetes. The recently described wide spectrum of action executed by this drug suggests a potential therapeutic benefit in a panoply of disorders. Current studies imply that metformin could play a neuroprotective role by reversing hallmarks of brain injury (metabolic dysfunction, neuronal dystrophy and cellular loss), in addition to cognitive and behavioral alterations that accompany the onset of certain brain diseases such as Alzheimer's disease (AD) and depression. However, the mechanisms by which metformin exerts its protective effect in neurodegenerative disorders are not yet fully elucidated. The aim of this review is to reexamine the mechanisms through which metformin performs its function while concentrating on its effect on reestablishing homeostasis in a metabolically disturbed milieu. We will also highlight the importance of metabolic stress, not only as a component of many neurological disorders, but also as a primary driving force for neural insult. Of interest, we will explore the involvement of metabolic stress in the pathobiology of AD and depression. The derangement in major metabolic pathways, including AMPK, insulin and glucose transporters, will be explored and the potential therapeutic effects of metformin administration on the reversal of brain injury in such metabolism dependent diseases will be exposed.
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Affiliation(s)
- Mohamed El Massry
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Lynn M Alaeddine
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Leen Ali
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Celine Saad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
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