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1
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Wu Z, Liu X, Wang Y, Zeng Z, Chen W, Li H. Pseudogene Lamr1-ps1 Aggravates Early Spatial Learning Memory Deficits in Alzheimer's Disease Model Mice. Neurosci Bull 2025; 41:600-614. [PMID: 39746896 PMCID: PMC11979086 DOI: 10.1007/s12264-024-01336-6] [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: 03/06/2024] [Accepted: 10/15/2024] [Indexed: 01/04/2025] Open
Abstract
Alzheimer's disease (AD), a neurodegenerative disorder with complex etiologies, manifests through a cascade of pathological changes before clinical symptoms become apparent. Among these early changes, alterations in the expression of non-coding RNAs (ncRNAs) have emerged as pivotal events. In this study, we focused on the aberrant expression of ncRNAs and revealed that Lamr1-ps1, a pseudogene of the laminin receptor, significantly exacerbates early spatial learning and memory deficits in APP/PS1 mice. Through a combination of bioinformatics prediction and experimental validation, we identified the miR-29c/Bace1 pathway as a potential regulatory mechanism by which Lamr1-ps1 influences AD pathology. Importantly, augmenting the miR-29c-3p levels in mice ameliorated memory deficits, underscoring the therapeutic potential of targeting miR-29c-3p in early AD intervention. This study not only provides new insights into the role of pseudogenes in AD but also consolidates a foundational basis for considering miR-29c as a viable therapeutic target, offering a novel avenue for AD research and treatment strategies.
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Affiliation(s)
- Zhuoze Wu
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637100, China
| | - Xiaojie Liu
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637100, China
| | - Yuntai Wang
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637100, China
- School of Clinical Medicine, North Sichuan Medical College, Nanchong, 637100, China
| | - Zimeng Zeng
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637100, China
| | - Wei Chen
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637100, China
| | - Hao Li
- Department of Pathophysiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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2
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Wu H, Li YL, Liu PM, Yang JJ. Global status and trends of exosomes in neurodegenerative diseases from 2014 to 2023: a bibliometric and visual analysis. Front Aging Neurosci 2025; 17:1496252. [PMID: 40134534 PMCID: PMC11933124 DOI: 10.3389/fnagi.2025.1496252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 02/25/2025] [Indexed: 03/27/2025] Open
Abstract
Background Neurodegenerative diseases (NDs) are chronic and progressive conditions that significantly impact global public health. Recent years have highlighted exosomes as key mechanisms involved in these diseases. This study aims to visualize and analyze the structure and content of exosomes in NDs based on past research to identify new research ideas and directions. Through bibliometric analysis, we assess the current state of research on exosomes in the field of NDs worldwide over the past decade, highlighting significant findings, major research areas, and emerging trends. Methods Publications on exosomes in NDs research were obtained from the Web of Science Core Collection (WOSCC) database. Eligible literature was analyzed using Bibliometric R, VOSviewer, and Citespace. Results Between 2014 and 2023, 2,393 publications on exosomes in NDs were included in the analysis. The number of relevant publications has been increasing yearly, with China leading in international collaboration, followed by the United States. And China has the largest number of academic scholars as leading and corresponding authors in all the countries, known as the great research society and community. Notable institutions contributing to these publications include Nia, the University of San Francisco California, and Capital Medical University, which rank highly in both publication volume and citations. Dimitrios Kapogiannis is a pivotal figure in the author collaboration network, having produced the highest number of publications (Sato et al., 2011) and amassed 3,921 citations. The journal with the most published articles in this field is The International Journal of Molecular Sciences, which has published 131 articles and received 3,347 citations. A recent analysis of keyword clusters indicates that "Exosome-like liposomes," "Independent mechanisms," and "Therapeutic potential" are emerging research hotspots. Conclusion This is the first bibliometric study to provide a comprehensive summary of the research trends and developments regarding exosomes in NDs studies. Future research in this area may explore the role of mesenchymal stromal cells, microRNAs (miRNAs), and targeted drug delivery systems to further investigate the underlying mechanisms and develop new therapeutics.
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Affiliation(s)
- Hao Wu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yao-lei Li
- National Institutes for Food and Drug Control, Beijing, China
| | - Pan-miao Liu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jian-jun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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3
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Kuznetsov NV, Statsenko Y, Ljubisavljevic M. An Update on Neuroaging on Earth and in Spaceflight. Int J Mol Sci 2025; 26:1738. [PMID: 40004201 PMCID: PMC11855577 DOI: 10.3390/ijms26041738] [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: 01/04/2025] [Revised: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Over 400 articles on the pathophysiology of brain aging, neuroaging, and neurodegeneration were reviewed, with a focus on epigenetic mechanisms and numerous non-coding RNAs. In particular, this review the accent is on microRNAs, the discovery of whose pivotal role in gene regulation was recognized by the 2024 Nobel Prize in Physiology or Medicine. Aging is not a gradual process that can be easily modeled and described. Instead, multiple temporal processes occur during aging, and they can lead to mosaic changes that are not uniform in pace. The rate of change depends on a combination of external and internal factors and can be boosted in accelerated aging. The rate can decrease in decelerated aging due to individual structural and functional reserves created by cognitive, physical training, or pharmacological interventions. Neuroaging can be caused by genetic changes, epigenetic modifications, oxidative stress, inflammation, lifestyle, and environmental factors, which are especially noticeable in space environments where adaptive changes can trigger aging-like processes. Numerous candidate molecular biomarkers specific to neuroaging need to be validated to develop diagnostics and countermeasures.
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Affiliation(s)
- Nik V. Kuznetsov
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (M.L.)
| | - Yauhen Statsenko
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (M.L.)
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Milos Ljubisavljevic
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (M.L.)
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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4
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Alhenaky A, Alhazmi S, Alamri SH, Alkhatabi HA, Alharthi A, Alsaleem MA, Abdelnour SA, Hassan SM. Exosomal MicroRNAs in Alzheimer's Disease: Unveiling Their Role and Pioneering Tools for Diagnosis and Treatment. J Clin Med 2024; 13:6960. [PMID: 39598105 PMCID: PMC11594708 DOI: 10.3390/jcm13226960] [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: 10/27/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024] Open
Abstract
Alzheimer's disease (AD) is a common neurodegenerative disorder that presents a significant health concern, often leading to substantial cognitive decline among older adults. A prominent feature of AD is progressive dementia, which eventually disrupts daily functioning and the ability to live independently. A major challenge in addressing AD is its prolonged pre-symptomatic phase, which makes early detection difficult. Moreover, the disease's complexity and the inefficiency of current diagnostic methods impede the development of targeted therapies. Therefore, there is an urgent need to enhance diagnostic methodologies for detection and treating AD even before clinical symptoms appear. Exosomes are nanoscale biovesicles secreted by cells, including nerve cells, into biofluids. These exosomes play essential roles in the central nervous system (CNS) by facilitating neuronal communication and thus influencing major physiological and pathological processes. Exosomal cargo, particularly microRNAs (miRNAs), are critical mediators in this cellular communication, and their dysregulation affects various pathological pathways related to neurodegenerative diseases, including AD. This review discusses the significant roles of exosomal miRNAs in the pathological mechanisms related to AD, focusing on the promising use of exosomal miRNAs as diagnostic biomarkers and targeted therapeutic interventions for this devastating disease.
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Affiliation(s)
- Alhanof Alhenaky
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Immunology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 80200, Saudi Arabia
| | - Safiah Alhazmi
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Immunology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 80200, Saudi Arabia
- Neuroscience and Geroscience Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 80200, Saudi Arabia
| | - Sultan H. Alamri
- Neuroscience and Geroscience Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 80200, Saudi Arabia
- Department of Family Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Heba A. Alkhatabi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 22254, Saudi Arabia
- Hematology Research Unit (HRU), King Fahd Medical Research Center, King Abdulaziz University, Jeddah 22254, Saudi Arabia
| | - Amani Alharthi
- Department of Biology, College of Science Al-Zulfi, Majmaah University, Majmaah 11952, Saudi Arabia
| | - Mansour A. Alsaleem
- Unit of Scientific Research, Applied College, Qassim University, Buraydah 52571, Saudi Arabia
| | - Sameh A. Abdelnour
- Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig 44519, Egypt
| | - Sabah M. Hassan
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Immunology Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 80200, Saudi Arabia
- Princess Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Genetics, Faculty of Agriculture, Ain Shams University, Cairo 11517, Egypt
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5
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Spinelli M, Spallotta F, Cencioni C, Natale F, Re A, Dellaria A, Farsetti A, Fusco S, Grassi C. High fat diet affects the hippocampal expression of miRNAs targeting brain plasticity-related genes. Sci Rep 2024; 14:19651. [PMID: 39179650 PMCID: PMC11343842 DOI: 10.1038/s41598-024-69707-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 08/06/2024] [Indexed: 08/26/2024] Open
Abstract
Metabolic disorders such as insulin resistance and type 2 diabetes are associated with brain dysfunction and cognitive deficits, although the underpinning molecular mechanisms remain elusive. Epigenetic factors, such as non-coding RNAs, have been reported to mediate the molecular effects of nutrient-related signals. Here, we investigated the changes of miRNA expression profile in the hippocampus of a well-established experimental model of metabolic disease induced by high fat diet (HFD). In comparison to the control group fed with standard diet, we observed 69 miRNAs exhibiting increased expression and 63 showing decreased expression in the HFD mice's hippocampus. Through bioinformatics analysis, we identified numerous potential targets of the dysregulated miRNAs, pinpointing a subset of genes regulating neuroplasticity that were targeted by multiple differentially modulated miRNAs. We also validated the expression of these synaptic and non-synaptic proteins, confirming the downregulation of Synaptotagmin 1 (SYT1), calcium/calmodulin dependent protein kinase I delta (CaMK1D), 2B subunit of N-methyl-D-aspartate glutamate receptor (GRIN2B), the DNA-binding protein Special AT-Rich Sequence-Binding Protein 2 (SATB2), and RNA-binding proteins Cytoplasmic polyadenylation element-binding protein 1 (CPEB1) and Neuro-oncological ventral antigen 1 (NOVA1) in the hippocampus of HFD mice. In summary, our study offers a snapshot of the HFD-related miRNA landscape potentially involved in the alterations of brain functions associated with metabolic disorders. By shedding light on the specific miRNA-mRNA interactions, our research contributes to a deeper understanding of the molecular mechanisms underlying the effects of HFD on the synaptic function.
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Affiliation(s)
- Matteo Spinelli
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy
| | - Francesco Spallotta
- Department of Biology and Biotechnologies Charles Darwin, Sapienza University, 00185, Rome, Italy
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00185, Rome, Italy
| | - Chiara Cencioni
- Institute for Systems Analysis and Computer Science "A. Ruberti", National Research Council (CNR-IASI), Rome, Italy
| | - Francesca Natale
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy
| | - Agnese Re
- Institute for Systems Analysis and Computer Science "A. Ruberti", National Research Council (CNR-IASI), Rome, Italy
- Dipartimento di Scienze Laboratoristiche ed Infettivologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
| | - Alice Dellaria
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
| | - Antonella Farsetti
- Institute for Systems Analysis and Computer Science "A. Ruberti", National Research Council (CNR-IASI), Rome, Italy
| | - Salvatore Fusco
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168, Rome, Italy.
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy.
| | - Claudio Grassi
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168, Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy
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Słowikowski B, Owecki W, Jeske J, Jezierski M, Draguła M, Goutor U, Jagodziński PP, Kozubski W, Dorszewska J. Epigenetics and the neurodegenerative process. Epigenomics 2024; 16:473-491. [PMID: 38511224 DOI: 10.2217/epi-2023-0416] [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: 03/22/2024] Open
Abstract
Neurological diseases are multifactorial, genetic and environmental. Environmental factors such as diet, physical activity and emotional state are epigenetic factors. Environmental markers are responsible for epigenetic modifications. The effect of epigenetic changes is increased inflammation of the nervous system and neuronal damage. In recent years, it has been shown that epigenetic changes may cause an increased risk of neurological disorders but, currently, the relationship between epigenetic modifications and neurodegeneration remains unclear. This review summarizes current knowledge about neurological disorders caused by epigenetic changes in diseases such as Alzheimer's disease, Parkinson's disease, stroke and epilepsy. Advances in epigenetic techniques may be key to understanding the epigenetics of central changes in neurological diseases.
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Affiliation(s)
- Bartosz Słowikowski
- Department of Biochemistry & Molecular Biology, Poznan University of Medical Sciences, Poznan, 61-701, Poland
| | - Wojciech Owecki
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, 61-701, Poland
| | - Jan Jeske
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, 61-701, Poland
| | - Michał Jezierski
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, 61-701, Poland
| | - Michał Draguła
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, 61-701, Poland
| | - Ulyana Goutor
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, 61-701, Poland
| | - Paweł P Jagodziński
- Department of Biochemistry & Molecular Biology, Poznan University of Medical Sciences, Poznan, 61-701, Poland
| | - Wojciech Kozubski
- Chair & Department of Neurology, Poznan University of Medical Sciences, Poznan, 61-701, Poland
| | - Jolanta Dorszewska
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, 61-701, Poland
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7
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Luan X, Xing H, Guo F, Liu W, Jiao Y, Liu Z, Wang X, Gao S. The role of ncRNAs in depression. Heliyon 2024; 10:e27307. [PMID: 38496863 PMCID: PMC10944209 DOI: 10.1016/j.heliyon.2024.e27307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 03/19/2024] Open
Abstract
Depressive disorders have a significant impact on public health, and depression have an unsatisfactory recurrence rate and are challenging to treat. Non-coding RNAs (ncRNAs) are RNAs that do not code protein, which have been shown to be crucial for transcriptional regulation. NcRNAs are important to the onset, progress and treatment of depression because they regulate various physiological functions. This makes them distinctively useful as biomarkers for diagnosing and tracking responses to therapy among individuals with depression. It is important to seek out and summarize the research findings on the impact of ncRNAs on depression since significant advancements have been made in this area recently. Hence, we methodically outlined the findings of published researches on ncRNAs and depression, focusing on microRNAs. Above all, this review aims to improve our understanding of ncRNAs and provide new insights of the diagnosis and treatment of depression.
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Affiliation(s)
- Xinchi Luan
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Han Xing
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Feifei Guo
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Weiyi Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Yang Jiao
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Zhenyu Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Xuezhe Wang
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Clinical Medicine, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
| | - Shengli Gao
- Biomedical Center, Qingdao Medical College, Qingdao University, Qingdao, Shandong, China
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8
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Paniri A, Hosseini MM, Akhavan-Niaki H. Alzheimer's Disease-Related Epigenetic Changes: Novel Therapeutic Targets. Mol Neurobiol 2024; 61:1282-1317. [PMID: 37700216 DOI: 10.1007/s12035-023-03626-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 08/30/2023] [Indexed: 09/14/2023]
Abstract
Aging is a significant risk factor for Alzheimer's disease (AD), although the precise mechanism and molecular basis of AD are not yet fully understood. Epigenetic mechanisms, such as DNA methylation and hydroxymethylation, mitochondrial DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), play a role in regulating gene expression related to neuron plasticity and integrity, which are closely associated with learning and memory development. This review describes the impact of dynamic and reversible epigenetic modifications and factors on memory and plasticity throughout life, emphasizing their potential as target for therapeutic intervention in AD. Additionally, we present insight from postmortem and animal studies on abnormal epigenetics regulation in AD, as well as current strategies aiming at targeting these factors in the context of AD therapy.
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Affiliation(s)
- Alireza Paniri
- Genetics Department, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
- Zoonoses Research Center, Pasteur Institute of Iran, Amol, Iran
| | | | - Haleh Akhavan-Niaki
- Genetics Department, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
- Zoonoses Research Center, Pasteur Institute of Iran, Amol, Iran.
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9
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Abdelmaksoud NM, Sallam AAM, Abulsoud AI, El-Dakroury WA, Abdel Mageed SS, Al-Noshokaty TM, Elrebehy MA, Elshaer SS, Mahmoud NA, Fathi D, Rizk NI, Elballal MS, Mohammed OA, Abdel-Reheim MA, Zaki MB, Saber S, Doghish AS. Unraveling the role of miRNAs in the diagnosis, progression, and therapeutic intervention of Alzheimer's disease. Pathol Res Pract 2024; 253:155007. [PMID: 38061270 DOI: 10.1016/j.prp.2023.155007] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 01/24/2024]
Abstract
Alzheimer's disease (AD) is a multifaceted, advancing neurodegenerative illness that is responsible for most cases of neurological impairment and dementia in the aged population. As the disease progresses, affected individuals may experience cognitive decline, linguistic problems, affective instability, and behavioral changes. The intricate nature of AD reflects the altered molecular mechanisms participating in the affected human brain. MicroRNAs (miRNAs, miR) are essential for the intricate control of gene expression in neurobiology. miRNAs exert their influence by modulating the transcriptome of brain cells, which typically exhibit substantial genetic activity, encompassing gene transcription and mRNA production. Presently, comprehensive studies are being conducted on AD to identify miRNA-based signatures that are indicative of the disease pathophysiology. These findings can contribute to the advancement of our understanding of the mechanisms underlying this disorder and can inform the development of therapeutic interventions based on miRNA and related RNA molecules. Therefore, this comprehensive review provides a detailed holistic analysis of the latest advances discussing the emerging role of miRNAs in the progression of AD and their possible application as potential biomarkers and targets for therapeutic interventions in future studies.
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Affiliation(s)
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Tohada M Al-Noshokaty
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Shereen Saeid Elshaer
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Naira Ali Mahmoud
- Microbiology and Immunology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Doaa Fathi
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Nehal I Rizk
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni, Suef 62521, Egypt.
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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10
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Kaur S, Verma H, Kaur S, Gangwar P, Yadav A, Yadav B, Rao R, Dhiman M, Mantha AK. Understanding the multifaceted role of miRNAs in Alzheimer's disease pathology. Metab Brain Dis 2024; 39:217-237. [PMID: 37505443 DOI: 10.1007/s11011-023-01265-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 07/16/2023] [Indexed: 07/29/2023]
Abstract
Small non-coding RNAs (miRNAs) regulate gene expression by binding to mRNA and mediating its degradation or inhibiting translation. Since miRNAs can regulate the expression of several genes, they have multiple roles to play in biological processes and human diseases. The majority of miRNAs are known to be expressed in the brain and are involved in synaptic functions, thus marking their presence and role in major neurodegenerative disorders, including Alzheimer's disease (AD). In AD, amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) are known to be the major hallmarks. The clearance of Aβ and tau is known to be associated with miRNA dysregulation. In addition, the β-site APP cleaving enzyme (BACE 1), which cleaves APP to form Aβ, is also found to be regulated by miRNAs, thus directly affecting Aβ accumulation. Growing evidences suggest that neuroinflammation can be an initial event in AD pathology, and miRNAs have been linked with the regulation of neuroinflammation. Inflammatory disorders have also been associated with AD pathology, and exosomes associated with miRNAs are known to regulate brain inflammation, suggesting for the role of systemic miRNAs in AD pathology. Several miRNAs have been related in AD, years before the clinical symptoms appear, most of which are associated with regulating the cell cycle, immune system, stress responses, cellular senescence, nerve growth factor (NGF) signaling, and synaptic regulation. Phytochemicals, especially polyphenols, alter the expression of various miRNAs by binding to miRNAs or binding to the transcriptional activators of miRNAs, thus control/alter various metabolic pathways. Awing to the sundry biological processes being regulated by miRNAs in the brain and regulation of expression of miRNAs via phytochemicals, miRNAs and the regulatory bioactive phytochemicals can serve as therapeutic agents in the treatment and management of AD.
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Affiliation(s)
- Sharanjot Kaur
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Harkomal Verma
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Sukhchain Kaur
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Prabhakar Gangwar
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Anuradha Yadav
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Bharti Yadav
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Rashmi Rao
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India
| | - Monisha Dhiman
- Department of Microbiology, School of Basic Sciences, Central University of Punjab, Ghudda, Bathinda, Punjab, India
| | - Anil Kumar Mantha
- Department of Zoology, School of Basic Sciences, Central University of Punjab, VPO - Ghudda, Bathinda, 151 401, Punjab, India.
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11
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Bandakinda M, Mishra A. Insights into role of microRNA in Alzheimer's disease: From contemporary research to bedside perspective. Int J Biol Macromol 2023; 253:126561. [PMID: 37659493 DOI: 10.1016/j.ijbiomac.2023.126561] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/20/2023] [Accepted: 08/18/2023] [Indexed: 09/04/2023]
Abstract
One of the most prevalent neurodegenerative disorders is Alzheimer's disease (AD). Despite the pervasiveness of AD being considerable, the rates of both diagnosis and therapy are comparatively less and still lacking. For the treatment of AD, acetylcholinesterase inhibitors and NMDA receptor antagonists (Memantine) have received clinical approval. The approved drugs are only capable of mitigating the symptoms; however, halting the progression of the disease remains a matter of substantial concern. MicroRNAs (miRs) are a subclass of non-coding single-stranded RNA molecules that target mRNAs to control the expression of genes in certain tissues. Dysregulation in the expression and function of miRs contributes to a neurodegeneration-like pathogenesis seen in Alzheimer's disease (AD), featuring hallmark characteristics such as Aβ aggregation, hyper-phosphorylation of Tau proteins, mitochondrial dysfunction, neuroinflammation, and apoptosis. These factors collectively underpin the cognitive deterioration and learning disabilities associated with AD. According to the research, numerous miRs have considerably different expression patterns in AD patients compared to healthy people. Due to these attributes, miRs prove to be effective diagnostic and therapeutic agents for AD. This review will examine clinical and preclinical data concerning the potential of miRs as diagnostic and therapeutic agents, utilizing various techniques (such as miR antagonists or inhibitors, miR agonists or mimics, miR sponges, and miR antisense oligonucleotides) to target specific pathogenic mechanisms in AD.
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Affiliation(s)
- Mounisha Bandakinda
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) - Guwahati, Changsari, Kamrup, Assam 781101, India
| | - Awanish Mishra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) - Guwahati, Changsari, Kamrup, Assam 781101, India.
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12
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Wang L, Shui X, Diao Y, Chen D, Zhou Y, Lee TH. Potential Implications of miRNAs in the Pathogenesis, Diagnosis, and Therapeutics of Alzheimer's Disease. Int J Mol Sci 2023; 24:16259. [PMID: 38003448 PMCID: PMC10671222 DOI: 10.3390/ijms242216259] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/10/2023] [Accepted: 11/12/2023] [Indexed: 11/26/2023] Open
Abstract
Alzheimer's disease (AD) is a complex multifactorial disorder that poses a substantial burden on patients, caregivers, and society. Considering the increased aging population and life expectancy, the incidence of AD will continue to rise in the following decades. However, the molecular pathogenesis of AD remains controversial, superior blood-based biomarker candidates for early diagnosis are still lacking, and effective therapeutics to halt or slow disease progression are urgently needed. As powerful genetic regulators, microRNAs (miRNAs) are receiving increasing attention due to their implications in the initiation, development, and theranostics of various diseases, including AD. In this review, we summarize miRNAs that directly target microtubule-associated protein tau (MAPT), amyloid precursor protein (APP), and β-site APP-cleaving enzyme 1 (BACE1) transcripts and regulate the alternative splicing of tau and APP. We also discuss related kinases, such as glycogen synthase kinase (GSK)-3β, cyclin-dependent kinase 5 (CDK5), and death-associated protein kinase 1 (DAPK1), as well as apolipoprotein E, that are directly targeted by miRNAs to control tau phosphorylation and amyloidogenic APP processing leading to Aβ pathologies. Moreover, there is evidence of miRNA-mediated modulation of inflammation. Furthermore, circulating miRNAs in the serum or plasma of AD patients as noninvasive biomarkers with diagnostic potential are reviewed. In addition, miRNA-based therapeutics optimized with nanocarriers or exosomes as potential options for AD treatment are discussed.
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Affiliation(s)
| | | | | | | | - Ying Zhou
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China; (L.W.)
| | - Tae Ho Lee
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China; (L.W.)
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13
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Shelash Al-Hawary SI, Yahya Ali A, Mustafa YF, Margiana R, Maksuda Ilyasovna S, Ramadan MF, Almalki SG, Alwave M, Alkhayyat S, Alsalamy A. The microRNAs (miRs) overexpressing mesenchymal stem cells (MSCs) therapy in neurological disorders; hope or hype. Biotechnol Prog 2023; 39:e3383. [PMID: 37642165 DOI: 10.1002/btpr.3383] [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: 06/25/2023] [Revised: 07/30/2023] [Accepted: 08/09/2023] [Indexed: 08/31/2023]
Abstract
Altered expression of multiple miRNAs was found to be extensively involved in the pathogenesis of different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. One of the biggest concerns within gene-based therapy is the delivery of the therapeutic microRNAs to the intended place, which is obligated to surpass the biological barriers without undergoing degradation in the bloodstream or renal excretion. Hence, the delivery of modified and unmodified miRNA molecules using excellent vehicles is required. In this light, mesenchymal stem cells (MSCs) have attracted increasing attention. The MSCs can be genetically modified to express or overexpress a particular microRNA aimed with promote neurogenesis and neuroprotection. The current review has focused on the therapeutic capabilities of microRNAs-overexpressing MSCs to ameliorate functional deficits in neurological conditions.
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Affiliation(s)
| | - Anas Yahya Ali
- Department of Nursing, Al-maarif University College, Ramadi, Al-Anbar, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | | | | | - Sami G Almalki
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, Saudi Arabia
| | - Marim Alwave
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Safa Alkhayyat
- College of Pharmacy, The Islamic University, Najaf, Iraq
| | - Ali Alsalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna, Iraq
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14
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Statsenko Y, Kuznetsov NV, Morozova D, Liaonchyk K, Simiyu GL, Smetanina D, Kashapov A, Meribout S, Gorkom KNV, Hamoudi R, Ismail F, Ansari SA, Emerald BS, Ljubisavljevic M. Reappraisal of the Concept of Accelerated Aging in Neurodegeneration and Beyond. Cells 2023; 12:2451. [PMID: 37887295 PMCID: PMC10605227 DOI: 10.3390/cells12202451] [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: 08/04/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND Genetic and epigenetic changes, oxidative stress and inflammation influence the rate of aging, which diseases, lifestyle and environmental factors can further accelerate. In accelerated aging (AA), the biological age exceeds the chronological age. OBJECTIVE The objective of this study is to reappraise the AA concept critically, considering its weaknesses and limitations. METHODS We reviewed more than 300 recent articles dealing with the physiology of brain aging and neurodegeneration pathophysiology. RESULTS (1) Application of the AA concept to individual organs outside the brain is challenging as organs of different systems age at different rates. (2) There is a need to consider the deceleration of aging due to the potential use of the individual structure-functional reserves. The latter can be restored by pharmacological and/or cognitive therapy, environment, etc. (3) The AA concept lacks both standardised terminology and methodology. (4) Changes in specific molecular biomarkers (MBM) reflect aging-related processes; however, numerous MBM candidates should be validated to consolidate the AA theory. (5) The exact nature of many potential causal factors, biological outcomes and interactions between the former and the latter remain largely unclear. CONCLUSIONS Although AA is commonly recognised as a perspective theory, it still suffers from a number of gaps and limitations that assume the necessity for an updated AA concept.
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Affiliation(s)
- Yauhen Statsenko
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Big Data Analytic Center, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Nik V. Kuznetsov
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
| | - Daria Morozova
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
| | - Katsiaryna Liaonchyk
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
| | - Gillian Lylian Simiyu
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Darya Smetanina
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Aidar Kashapov
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Sarah Meribout
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Klaus Neidl-Van Gorkom
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Rifat Hamoudi
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK
| | - Fatima Ismail
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Suraiya Anjum Ansari
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Bright Starling Emerald
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Milos Ljubisavljevic
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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15
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Datta N, Johnson C, Kao D, Gurnani P, Alexander C, Polytarchou C, Monaghan TM. MicroRNA-based therapeutics for inflammatory disorders of the microbiota-gut-brain axis. Pharmacol Res 2023; 194:106870. [PMID: 37499702 DOI: 10.1016/j.phrs.2023.106870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 07/22/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023]
Abstract
An emerging but less explored shared pathophysiology across microbiota-gut-brain axis disorders is aberrant miRNA expression, which may represent novel therapeutic targets. miRNAs are small, endogenous non-coding RNAs that are important transcriptional repressors of gene expression. Most importantly, they regulate the integrity of the intestinal epithelial and blood-brain barriers and serve as an important communication channel between the gut microbiome and the host. A well-defined understanding of the mode of action, therapeutic strategies and delivery mechanisms of miRNAs is pivotal in translating the clinical applications of miRNA-based therapeutics. Accumulating evidence links disorders of the microbiota-gut-brain axis with a compromised gut-blood-brain-barrier, causing gut contents such as immune cells and microbiota to enter the bloodstream leading to low-grade systemic inflammation. This has the potential to affect all organs, including the brain, causing central inflammation and the development of neurodegenerative and neuropsychiatric diseases. In this review, we have examined in detail miRNA biogenesis, strategies for therapeutic application, delivery mechanisms, as well as their pathophysiology and clinical applications in inflammatory gut-brain disorders. The research data in this review was drawn from the following databases: PubMed, Google Scholar, and Clinicaltrials.gov. With increasing evidence of the pathophysiological importance for miRNAs in microbiota-gut-brain axis disorders, therapeutic targeting of cross-regulated miRNAs in these disorders displays potentially transformative and translational potential. Further preclinical research and human clinical trials are required to further advance this area of research.
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Affiliation(s)
- Neha Datta
- School of Medicine, University of Nottingham, Nottingham, UK
| | - Charlotte Johnson
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Dina Kao
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Pratik Gurnani
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Cameron Alexander
- Division of Molecular Therapeutics & Formulation, School of Pharmacy, University of Nottingham, Nottingham, UK
| | - Christos Polytarchou
- Department of Biosciences, John van Geest Cancer Research Centre, School of Science & Technology, Nottingham Trent University, Nottingham, UK.
| | - Tanya M Monaghan
- NIHR Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
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16
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Li B, Lu Y, Wang R, Xu T, Lei X, Jin H, Gao X, Xie Y, Liu X, Zeng J. MiR-29c Inhibits TNF-α-Induced ROS Production and Apoptosis in Mouse Hippocampal HT22 Cell Line. Neurochem Res 2023; 48:519-536. [PMID: 36309937 DOI: 10.1007/s11064-022-03776-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 07/18/2022] [Accepted: 09/29/2022] [Indexed: 02/04/2023]
Abstract
Recent reports have suggested that abnormal miR-29c expression in hippocampus have been implicated in the pathophysiology of some neurodegenerative and neuropsychiatric diseases. However, the underlying effect of miR-29c in regulating hippocampal neuronal function is not clear. In this study, HT22 cells were infected with lentivirus containing miR-29c or miR-29c sponge. Cell counting kit-8 (CCK8) and lactate dehydrogenase (LDH) assay kit were applied to evaluate cell viability and toxicity before and after TNF-α administration. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Hoechst 33258 staining and TUNEL assay were used to evaluate cell apoptosis. The expression of key mRNA/proteins (TNFR1, Bcl-2, Bax, TRADD, FADD, caspase-3, -8 and -9) in the apoptosis pathway was detected by PCR or WB. In addition, the protein expression of microtubule-associated protein-2 (MAP-2), nerve growth-associated protein 43 (GAP-43) and synapsin-1 (SYN-1) was detected by WB. As a result, we found that miR-29c overexpression could improve cell viability, attenuate LDH release, reduce ROS production and inhibit MMP depolarization in TNF-α-treated HT22 cells. Furthermore, miR-29c overexpression was found to decrease apoptotic rate, along with decreased expression of Bax, cleaved caspase-3, cleaved caspase-9, and increased expression of Bcl-2 in TNF-α-treated HT22 cells. However, miR-29c sponge exhibited an opposite effects. In addition, in TNF-α-treated HT22 cells, miR-29c overexpression could decrease the expressions of TNFR1, TRADD, FADD and cleaved caspase-8. However, in HT22 cells transfected with miR-29c sponge, TNF-α-induced the expressions of TNFR1, TRADD, FADD and cleaved caspase-8 was significantly exacerbated. At last, TNF-α-induced the decreased expression of MAP-2, GAP-43 and SYN-1 was reversed by miR-29c but exacerbated by miR-29c sponge. Overall, our study demonstrated that miR-29c protects against TNF-α-induced HT22 cells injury through alleviating ROS production and reduce neuronal apoptosis. Therefore, miR-29c might be a potential therapeutic agent for TNF-α accumulation and toxicity-related brain diseases.
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Affiliation(s)
- Bo Li
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Ying Lu
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Rong Wang
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Tao Xu
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Xiaolu Lei
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Huan Jin
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Xiaohong Gao
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Ye Xie
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Xiaohong Liu
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China
| | - Junwei Zeng
- Department of Physiology, Zunyi Medical University, Zunyi, 563000, Guizhou, China.
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17
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Elzayat EM, Shahien SA, El-Sherif AA, Hosney M. miRNAs and Stem Cells as Promising Diagnostic and Therapeutic Targets for Alzheimer's Disease. J Alzheimers Dis 2023; 94:S203-S225. [PMID: 37212107 PMCID: PMC10473110 DOI: 10.3233/jad-221298] [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: 03/30/2023] [Indexed: 05/23/2023]
Abstract
Alzheimer's disease (AD) is a cumulative progressive neurodegenerative disease characterized mainly by impairment in cognitive functions accompanied by memory loss, disturbance in behavior and personality, and difficulties in learning. Although the main causes of AD pathogenesis are not fully understood yet, amyloid-β peptides and tau proteins are supposed to be responsible for AD onset and pathogenesis. Various demographic, genetic, and environmental risk factors are involved in AD onset and pathogenesis such as age, gender, several genes, lipids, malnutrition, and poor diet. Significant changes were observed in microRNA (miRNA) levels between normal and AD cases giving hope for a diagnostic procedure for AD through a simple blood test. As yet, only two classes of AD therapeutic drugs are approved by FDA. They are classified as acetylcholinesterase inhibitors and N-methyl-D-aspartate antagonists (NMDA). Unfortunately, they can only treat the symptoms but cannot cure AD or stop its progression. New therapeutic approaches were developed for AD treatment including acitretin due to its ability to cross blood-brain barrier in the brain of rats and mice and induce the expression of ADAM 10 gene, the α-secretase of human amyloid-β protein precursor, stimulating the non-amyloidogenic pathway for amyloid-β protein precursor processing resulting in amyloid-β reduction. Also stem cells may have a crucial role in AD treatment as they can improve cognitive functions and memory in AD rats through regeneration of damaged neurons. This review spotlights on promising diagnostic techniques such as miRNAs and therapeutic approaches such as acitretin and/or stem cells keeping in consideration AD pathogenesis, stages, symptoms, and risk factors.
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Affiliation(s)
- Emad M. Elzayat
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Sherif A. Shahien
- Biotechnology/Bimolecular Chemistry Program, Faculty of Science, Helwan University, Cairo, Egypt
| | - Ahmed A. El-Sherif
- Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
| | - Mohamed Hosney
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt
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18
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Li Y, Wang H, Chen L, Wei K, Liu Y, Han Y, Xia X. Circ_0003611 regulates apoptosis and oxidative stress injury of Alzheimer's disease via miR-383-5p/KIF1B axis. Metab Brain Dis 2022; 37:2915-2924. [PMID: 35960460 DOI: 10.1007/s11011-022-01051-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 07/07/2022] [Indexed: 10/15/2022]
Abstract
Alzheimer's disease (AD) is a high incidence neurodegenerative disease. Emerging evidence suggests that circular RNAs (circRNAs) play an important modulator in the pathogenesis of AD. The aim of this paper was to reconnoiter the effects of circular RNA_0003611 (circ_0003611) on Aβ-triggered neuronal injury in AD. In this work, the abundance of circ_0003611 was augmented in AD patients and SH-SY5Y and SK-N-SH cells treated with Aβ. Aβ-mediated cell proliferation, apoptosis, inflammatory response, oxidative stress, and glycolysis were abolished through circ_0003611 silencing. Circ_0003611 worked as a miR-383-5p sponge, and the protective role of circ_0003611 absence on Aβ-triggered neuronal injury was overturned by releasing miR-383-5p. Meanwhile, miR-383-5p directly targeted KIF1B, and miR-383-5p upregulation might relieve Aβ-triggered neuronal injury by reducing KIF1B expression. Mechanical analysis discovered that circ_0003611 served as a sponge of miR-383-5p to impact KIF1B expression. These findings indicated that circ_0003611 improved Aβ-triggered neuronal injury in AD through targeting the miR-383-5p/KIF1B axis, which might deliver innovative therapy targeting for AD.
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Affiliation(s)
- Yong Li
- Sport and Health College of Guangxi Normal University, Guilin, China
| | - Hongli Wang
- Sport and Health College of Guangxi Normal University, Guilin, China
| | - Li Chen
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, No.15 Lequn Road, Xiufeng District, Guilin, China
| | - Kailun Wei
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, No.15 Lequn Road, Xiufeng District, Guilin, China
| | - Yang Liu
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, No.15 Lequn Road, Xiufeng District, Guilin, China
| | - Yanbai Han
- Sport and Health College of Guangxi Normal University, Guilin, China
| | - Xuewei Xia
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, No.15 Lequn Road, Xiufeng District, Guilin, China.
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19
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Sundaramoorthy TH, Castanho I. The Neuroepigenetic Landscape of Vertebrate and Invertebrate Models of Neurodegenerative Diseases. Epigenet Insights 2022; 15:25168657221135848. [PMID: 36353727 PMCID: PMC9638687 DOI: 10.1177/25168657221135848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022] Open
Abstract
Vertebrate and invertebrate models of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, have been paramount to our understanding of the pathophysiology of these conditions; however, the brain epigenetic landscape is less well established in these disease models. DNA methylation, histone modifications, and microRNAs are among commonly studied mechanisms of epigenetic regulation. Genome-wide studies and candidate studies of specific methylation marks, histone marks, and microRNAs have demonstrated the dysregulation of these mechanisms in models of neurodegenerative diseases; however, the studies to date are scarce and inconclusive and the implications of many of these changes are still not fully understood. In this review, we summarize epigenetic changes reported to date in the brain of vertebrate and invertebrate models used to study neurodegenerative diseases, specifically diseases affecting the aging population. We also discuss caveats of epigenetic research so far and the use of disease models to understand neurodegenerative diseases, with the aim of improving the use of model organisms in this context in future studies.
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Affiliation(s)
| | - Isabel Castanho
- University of Exeter Medical School,
University of Exeter, Exeter, UK
- Beth Israel Deaconess Medical Center,
Boston, MA, USA
- Harvard Medical School, Boston, MA,
USA
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20
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Abuelezz NZ, Nasr FE, Abdel Aal WM, Molokhia T, Zaky A. Sera miR-34a, miR-29b and miR-181c as potential novel diagnostic biomarker panel for Alzheimers in the Egyptian population. Exp Gerontol 2022; 169:111961. [PMID: 36155067 DOI: 10.1016/j.exger.2022.111961] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 08/26/2022] [Accepted: 09/20/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Till date, there is an obvious obscurity of specific and early diagnostic biomarkers for Alzheimer's disease (AD). The promising diagnostic potential of serum miRNAs is increasingly emerging; however, rare miRNAs data originates from middle and low-income countries to provide proper validation in these highly affected populations. This study evaluated the diagnostic value of serum miR-34a, miR-29b and miR-181c in Egyptian AD patients. METHODS Expression levels of serum miR-34a, miR-29b and miR-181c were determined using quantitative real time PCR in AD patients versus healthy controls. Amyloid Beta 42 (Aβ42), Phosphorylated Tau (p-Tau) and TNF-α levels were also detected as distinctive AD markers. We further explored the correlation between miRNAs levels and Mini mental state examination (MMSE) scores. Finally, we conducted logistic regression and ROC curve analyses to evaluate the diagnostic values of the measured parameters. RESULTS Sera miR-34a, miR-29b and miR-181c were significantly downregulated in AD patients and this decrease was associated with cognitive decline. AD patients manifested significant elevation of Aβ42, pTau and TNF-α levels. The measured miRNAs showed good AD diagnostic value solely and when used together (AUC = 0.77, 95 % C·I. 0.62-0.93 at p < 0.01). Interestingly, combining miRNAs panel with Aβ42, TNF-α and pTau levels remarkably increased the diagnostic power (AUC = 0.97, 95 % C·I. 0.94-1.00 at p < 0.001) achieving sensitivity 88.2 % and specificity 91.4 %. CONCLUSION This study spots for the first time the diagnostic potential of serum miR-34a, miR-29b and miR-181c as minimally invasive AD biomarker panel in Egyptian patients and highlights their contribution in AD pathogenesis.
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Affiliation(s)
- Nermeen Z Abuelezz
- Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza, Egypt.
| | - Fayza Eid Nasr
- Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
| | | | - Tarek Molokhia
- Department of Psychiatry, School of Medicine, Alexandria University, Alexandria, Egypt
| | - Amira Zaky
- Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
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21
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Li S, Lei Z, Sun T. The role of microRNAs in neurodegenerative diseases: a review. Cell Biol Toxicol 2022; 39:53-83. [PMID: 36125599 PMCID: PMC9486770 DOI: 10.1007/s10565-022-09761-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 08/26/2022] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) are non-coding RNAs which are essential post-transcriptional gene regulators in various neuronal degenerative diseases and playact a key role in these physiological progresses. Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and, stroke, are seriously threats to the life and health of all human health and life kind. Recently, various studies have reported that some various miRNAs can regulate the development of neurodegenerative diseases as well as act as biomarkers to predict these neuronal diseases conditions. Endogenic miRNAs such as miR-9, the miR-29 family, miR-15, and the miR-34 family are generally dysregulated in animal and cell models. They are involved in regulating the physiological and biochemical processes in the nervous system by targeting regulating different molecular targets and influencing a variety of pathways. Additionally, exogenous miRNAs derived from homologous plants and defined as botanmin, such as miR2911 and miR168, can be taken up and transferred by other species to be and then act analogously to endogenic miRNAs to regulate the physiological and biochemical processes. This review summarizes the mechanism and principle of miRNAs in the treatment of some neurodegenerative diseases, as well as discusses several types of miRNAs which were the most commonly reported in diseases. These miRNAs could serve as a study provided some potential biomarkers in neurodegenerative diseases might be an ideal and/or therapeutic targets for neurodegenerative diseases. Finally, the role accounted of the prospective exogenous miRNAs involved in mammalian diseases is described.
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Affiliation(s)
- Shijie Li
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan, 430070, China
| | - Zhixin Lei
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan, 430070, China.
| | - Taolei Sun
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan, 430070, China. .,State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan, 430070, China.
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22
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Plasma microRNAs as potential biomarkers in early Alzheimer disease expression. Sci Rep 2022; 12:15589. [PMID: 36114255 PMCID: PMC9481579 DOI: 10.1038/s41598-022-19862-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/06/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractThe microRNAs (miRNAs) are potential biomarkers for complex pathologies due to their involvement in the regulation of several pathways. Alzheimer Disease (AD) requires new biomarkers in minimally invasive samples that allow an early diagnosis. The aim of this work is to study miRNAS as potential AD biomarkers and their role in the pathology development. In this study, participants (n = 46) were classified into mild cognitive impairment due to AD (MCI-AD, n = 19), preclinical AD (n = 8) and healthy elderly controls (n = 19), according to CSF biomarkers levels (amyloid β42, total tau, phosphorylated tau) and neuropsychological assessment. Then, plasma miRNAomic expression profiles were analysed by Next Generation Sequencing. Finally, the selected miRNAs were validated by quantitative PCR (q-PCR). A panel of 11 miRNAs was selected from omics expression analysis, and 8 of them were validated by q-PCR. Individually, they did not show statistically significant differences among participant groups. However, a multivariate model including these 8 miRNAs revealed a potential association with AD for three of them. Specifically, relatively lower expression levels of miR-92a-3p and miR-486-5p are observed in AD patients, and relatively higher levels of miR-29a-3p are observed in AD patients. These biomarkers could be involved in the regulation of pathways such as synaptic transmission, structural functions, cell signalling and metabolism or transcription regulation. Some plasma miRNAs (miRNA-92a-3p, miRNA-486-5p, miRNA-29a-3p) are slightly dysregulated in AD, being potential biomarkers of the pathology. However, more studies with a large sample size should be carried out to verify these results, as well as to further investigate the mechanisms of action of these miRNAs.
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23
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Varesi A, Carrara A, Pires VG, Floris V, Pierella E, Savioli G, Prasad S, Esposito C, Ricevuti G, Chirumbolo S, Pascale A. Blood-Based Biomarkers for Alzheimer's Disease Diagnosis and Progression: An Overview. Cells 2022; 11:1367. [PMID: 35456047 PMCID: PMC9044750 DOI: 10.3390/cells11081367] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 01/10/2023] Open
Abstract
Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1-42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease.
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Affiliation(s)
- Angelica Varesi
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
- Almo Collegio Borromeo, 27100 Pavia, Italy
| | - Adelaide Carrara
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (A.C.); (V.F.)
| | - Vitor Gomes Pires
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA;
| | - Valentina Floris
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (A.C.); (V.F.)
| | - Elisa Pierella
- School of Medicine, Faculty of Clinical and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK;
| | - Gabriele Savioli
- Emergency Department, IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Sakshi Prasad
- Faculty of Medicine, National Pirogov Memorial Medical University, 21018 Vinnytsya, Ukraine;
| | - Ciro Esposito
- Unit of Nephrology and Dialysis, ICS Maugeri, University of Pavia, 27100 Pavia, Italy;
| | - Giovanni Ricevuti
- Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37129 Verona, Italy;
| | - Alessia Pascale
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy;
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24
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De Sousa RAL, Improta-Caria AC. Regulation of microRNAs in Alzheimer´s disease, type 2 diabetes, and aerobic exercise training. Metab Brain Dis 2022; 37:559-580. [PMID: 35075500 DOI: 10.1007/s11011-022-00903-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022]
Abstract
Alzheimer's disease (AD) is the most common type of dementia. The evolution and aggregation of amyloid beta (β) oligomers is linked to insulin resistance in AD, which is also the major characteristic of type 2 diabetes (T2D). Being physically inactive can contribute to the development of AD and/or T2D. Aerobic exercise training (AET), a type of physical exercise, can be useful in preventing or treating the negative outcomes of AD and T2D. AD, T2D and AET can regulate the expression of microRNAs (miRNAs). Here, we review some of the changes in miRNAs expression regulated by AET, AD and T2D. MiRNAs play an important role in the gene regulation of key signaling pathways in both pathologies, AD and T2D. MiRNA dysregulation is evident in AD and has been associated with several neuropathological alterations, such as the development of a reactive gliosis. Expression of miRNAs are associated with many pathophysiological mechanisms involved in T2D like insulin synthesis, insulin resistance, glucose intolerance, hyperglycemia, intracellular signaling, and lipid profile. AET regulates miRNAs levels. We identified 5 miRNAs (miR-21, miR-29a/b, miR-103, miR-107, and miR-195) that regulate gene expression and are modulated by AET on AD and T2D. The identified miRNAs are potential targets to treat the symptoms of AD and T2D. Thus, AET is a non-pharmacological tool that can be used to prevent and fight the negative outcomes in AD and T2D.
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Affiliation(s)
- Ricardo Augusto Leoni De Sousa
- Programa Multicêntrico de Pós-Graduação Em Ciências Fisiológicas- Sociedade Brasileira de Fisiologia (SBFis), Universidade Federal Dos Vales Do Jequitinhonha E Mucuri (UFVJM), Campus JK, Rodovia MGT 367, Km 583, Alto da Jacuba, nº 5000, Diamantina, Minas Gerais, CEP 39100-000, Brazil.
| | - Alex Cleber Improta-Caria
- Post-Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Bahia, Brazil
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25
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Co-Expression Analysis of microRNAs and Proteins in Brain of Alzheimer's Disease Patients. Cells 2022; 11:cells11010163. [PMID: 35011725 PMCID: PMC8750061 DOI: 10.3390/cells11010163] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/29/2021] [Accepted: 01/01/2022] [Indexed: 02/04/2023] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia globally; however, the aetiology of AD remains elusive hindering the development of effective therapeutics. MicroRNAs (miRNAs) are regulators of gene expression and have been of growing interest in recent studies in many pathologies including AD not only for their use as biomarkers but also for their implications in the therapeutic field. In this study, miRNA and protein profiles were obtained from brain tissues of different stage (Braak III-IV and Braak V-VI) of AD patients and compared to matched controls. The aim of the study was to identify in the late stage of AD, the key dysregulated pathways that may contribute to pathogenesis and then to evaluate whether any of these pathways could be detected in the early phase of AD, opening new opportunity for early treatment that could stop or delay the pathology. Six common pathways were found regulated by miRNAs and proteins in the late stage of AD, with one of them (Rap1 signalling) activated since the early phase. MiRNAs and proteins were also compared to explore an inverse trend of expression which could lead to the identification of new therapeutic targets. These results suggest that specific miRNA changes could represent molecular fingerprint of neurodegenerative processes and potential therapeutic targets for early intervention.
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26
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Hashizume S, Nakano M, Kubota K, Sato S, Himuro N, Kobayashi E, Takaoka A, Fujimiya M. Mindfulness intervention improves cognitive function in older adults by enhancing the level of miRNA-29c in neuron-derived extracellular vesicles. Sci Rep 2021; 11:21848. [PMID: 34750393 PMCID: PMC8575875 DOI: 10.1038/s41598-021-01318-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 10/26/2021] [Indexed: 01/13/2023] Open
Abstract
Although mindfulness-based stress reduction (MBSR) improves cognitive function, the mechanism is not clear. In this study, people aged 65 years and older were recruited from elderly communities in Chitose City, Japan, and assigned to a non-MBSR group or a MBSR group. Before and after the intervention, the Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered, and blood samples were collected. Then, neuron-derived extracellular vesicles (NDEVs) were isolated from blood samples, and microRNAs, as well as the target mRNAs, were evaluated in NDEVs. A linear mixed model analysis showed significant effects of the MBSR x time interaction on the MoCA-J scores, the expression of miRNA(miR)-29c, DNA methyltransferase 3 alpha (DNMT3A), and DNMT3B in NDEVs. These results indicate that MBSR can improve cognitive function by increasing the expression of miR-29c and decreasing the expression of DNMT3A, as well as DNMT3B, in neurons. It was also found that intracerebroventricular injection of miR-29c mimic into 5xFAD mice prevented cognitive decline, as well as neuronal loss in the subiculum area, by down-regulating Dnmt3a and Dnmt3b in the hippocampus. The present study suggests that MBSR can prevent neuronal loss and cognitive impairment by increasing the neuronal expression of miR-29c.
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Affiliation(s)
- Shin Hashizume
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan
| | - Masako Nakano
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan.
| | - Kenta Kubota
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan
- Department of Physical Therapy, Hokkaido Chitose Rehabilitation College, Chitose, Hokkaido, Japan
| | - Seiichi Sato
- Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Nobuaki Himuro
- Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
| | - Eiji Kobayashi
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan
- Department of Physical Therapy, Faculty of Human Science, Hokkaido Bunkyo University, Eniwa, Hokkaido, Japan
| | - Akinori Takaoka
- Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Mineko Fujimiya
- Department of Anatomy, Sapporo Medical University School of Medicine, W17, S1, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan
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27
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Walgrave H, Zhou L, De Strooper B, Salta E. The promise of microRNA-based therapies in Alzheimer's disease: challenges and perspectives. Mol Neurodegener 2021; 16:76. [PMID: 34742333 PMCID: PMC8572071 DOI: 10.1186/s13024-021-00496-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 10/17/2021] [Indexed: 02/06/2023] Open
Abstract
Multi-pathway approaches for the treatment of complex polygenic disorders are emerging as alternatives to classical monotarget therapies and microRNAs are of particular interest in that regard. MicroRNA research has come a long way from their initial discovery to the cumulative appreciation of their regulatory potential in healthy and diseased brain. However, systematic interrogation of putative therapeutic or toxic effects of microRNAs in (models of) Alzheimer's disease is currently missing and fundamental research findings are yet to be translated into clinical applications. Here, we review the literature to summarize the knowledge on microRNA regulation in Alzheimer's pathophysiology and to critically discuss whether and to what extent these increasing insights can be exploited for the development of microRNA-based therapeutics in the clinic.
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Affiliation(s)
- Hannah Walgrave
- VIB Center for Brain & Disease Research, Leuven, KU, Leuven, Belgium
- Department of Neurosciences, Leuven Brain Institute, Leuven, Belgium
| | - Lujia Zhou
- Division of Janssen Pharmaceutica NV, Discovery Neuroscience, Janssen Research and Development, Beerse, Belgium
| | - Bart De Strooper
- VIB Center for Brain & Disease Research, Leuven, KU, Leuven, Belgium
- Department of Neurosciences, Leuven Brain Institute, Leuven, Belgium
- UK Dementia Research Institute at University College London, London, UK
| | - Evgenia Salta
- Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
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Systematic Search for Novel Circulating Biomarkers Associated with Extracellular Vesicles in Alzheimer's Disease: Combining Literature Screening and Database Mining Approaches. J Pers Med 2021; 11:jpm11100946. [PMID: 34683087 PMCID: PMC8538213 DOI: 10.3390/jpm11100946] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/13/2021] [Accepted: 09/19/2021] [Indexed: 12/12/2022] Open
Abstract
miRNAs play an important role in neurodegenerative diseases. Many miRNA-target gene interactions (MTI) have been experimentally confirmed and associated with Alzheimer’s disease (AD). miRNAs may also be contained within extracellular vesicles (EVs), mediators of cellular communication and a potential source of circulating biomarkers in body fluids. Therefore, EV-associated miRNAs (EV-miRNAs) in peripheral blood could support earlier and less invasive AD diagnostics. We aimed to prioritize EV-related miRNA with AD-related genes and to identify the most promising candidates for novel AD biomarkers. A list of unique EV-miRNAs from the literature was combined with a known set of AD risk genes and enriched for MTI. Additionally, miRNAs associated with the AD phenotype were combined with all known target genes in MTI enrichment. Expression in different sample types was analyzed to identify AD-associated miRNAs with the greatest potential as AD circulating biomarkers. Four common MTI were observed between EV-miRNAs and AD-associated miRNAs: hsa-miR-375–APH1B, hsa-miR-107–CDC42SE2, hsa-miR-375–CELF2, and hsa-miR-107–IL6. An additional 61 out of 169 unique miRNAs (36.1%) and seven out of 84 unique MTI (8.3%), observed in the body fluids of AD patients, were proposed as very strong AD-circulating biomarker candidates. Our analysis summarized several potential novel AD biomarkers, but further studies are needed to evaluate their potential in clinical practice.
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New RNA-Based Breakthroughs in Alzheimer's Disease Diagnosis and Therapeutics. Pharmaceutics 2021; 13:pharmaceutics13091397. [PMID: 34575473 PMCID: PMC8471423 DOI: 10.3390/pharmaceutics13091397] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 01/25/2023] Open
Abstract
Dementia is described as the fifth leading cause of death worldwide and Alzheimer’s disease (AD) is recognized as the most common, causing a huge impact on health costs and quality of patients’ lives. The main hallmarks that are commonly associated with the pathologic process are amyloid deposition, pathologic Tau phosphorylation and neurodegeneration. It is still unclear how these events are linked to the disease progression, due to the complex pathologic mechanisms. Nevertheless, several hypotheses have been proposed for a better understanding of AD. The AD diagnosis is performed by using a combination of several tools to detect β-amyloid peptide (Aβ) deposits and modifications in cognitive performance, sometimes being expensive and invasive. In the treatment field, there is still an absence of effective treatments to delay or stop the progression of the disease, with most of the approved drugs used to relieve symptoms, and all of them with significant adverse side effects. Considering all limitations, the need to establish new and more effective diagnostic and therapeutic strategies becomes clear. This review aims not only to describe the disease and its impact but also to collect the currently available diagnostic and therapeutic strategies, highlighting new promising RNA-based strategies for AD.
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Yuen SC, Liang X, Zhu H, Jia Y, Leung SW. Prediction of differentially expressed microRNAs in blood as potential biomarkers for Alzheimer's disease by meta-analysis and adaptive boosting ensemble learning. Alzheimers Res Ther 2021; 13:126. [PMID: 34243793 PMCID: PMC8272278 DOI: 10.1186/s13195-021-00862-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 06/17/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Blood circulating microRNAs that are specific for Alzheimer's disease (AD) can be identified from differentially expressed microRNAs (DEmiRNAs). However, non-reproducible and inconsistent reports of DEmiRNAs hinder biomarker development. The most reliable DEmiRNAs can be identified by meta-analysis. To enrich the pool of DEmiRNAs for potential AD biomarkers, we used a machine learning method called adaptive boosting for miRNA disease association (ABMDA) to identify eligible candidates that share similar characteristics with the DEmiRNAs identified from meta-analysis. This study aimed to identify blood circulating DEmiRNAs as potential AD biomarkers by augmenting meta-analysis with the ABMDA ensemble learning method. METHODS Studies on DEmiRNAs and their dysregulation states were corroborated with one another by meta-analysis based on a random-effects model. DEmiRNAs identified by meta-analysis were collected as positive examples of miRNA-AD pairs for ABMDA ensemble learning. ABMDA identified similar DEmiRNAs according to a set of predefined criteria. The biological significance of all resulting DEmiRNAs was determined by their target genes according to pathway enrichment analyses. The target genes common to both meta-analysis- and ABMDA-identified DEmiRNAs were collected to construct a network to investigate their biological functions. RESULTS A systematic database search found 7841 studies for an extensive meta-analysis, covering 54 independent comparisons of 47 differential miRNA expression studies, and identified 18 reliable DEmiRNAs. ABMDA ensemble learning was conducted based on the meta-analysis results and the Human MicroRNA Disease Database, which identified 10 additional AD-related DEmiRNAs. These 28 DEmiRNAs and their dysregulated pathways were related to neuroinflammation. The dysregulated pathway related to neuronal cell cycle re-entry (CCR) was the only statistically significant pathway of the ABMDA-identified DEmiRNAs. In the biological network constructed from 1865 common target genes of the identified DEmiRNAs, the multiple core ubiquitin-proteasome system, that is involved in neuroinflammation and CCR, was highly connected. CONCLUSION This study identified 28 DEmiRNAs as potential AD biomarkers in blood, by meta-analysis and ABMDA ensemble learning in tandem. The DEmiRNAs identified by meta-analysis and ABMDA were significantly related to neuroinflammation, and the ABMDA-identified DEmiRNAs were related to neuronal CCR.
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Affiliation(s)
- Sze Chung Yuen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, 999078 Macao China
| | - Xiaonan Liang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, 999078 Macao China
| | - Hongmei Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, 999078 Macao China
| | - Yongliang Jia
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, 999078 Macao China
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan China
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Siu-wai Leung
- Shenzhen Institute of Artificial Intelligence and Robotics for Society, Shenzhen, China
- Edinburgh Bayes Centre for AI Research in Shenzhen, College of Science and Engineering, University of Edinburgh, Edinburgh, Scotland, UK
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31
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Sharma VK, Mehta V, Singh TG. Alzheimer's Disorder: Epigenetic Connection and Associated Risk Factors. Curr Neuropharmacol 2021; 18:740-753. [PMID: 31989902 PMCID: PMC7536832 DOI: 10.2174/1570159x18666200128125641] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Revised: 11/26/2019] [Accepted: 01/27/2020] [Indexed: 12/13/2022] Open
Abstract
The gene based therapeutics and drug targets have shown incredible and appreciable advances in alleviating human sufferings and complexities. Epigenetics simply means above genetics or which controls the organism beyond genetics. At present it is very clear that all characteristics of an individual are not determined by DNA alone, rather the environment, stress, life style and nutrition play a vital part in determining the response of an organism. Thus, nature (genetic makeup) and nurture (exposure) play equally important roles in the responses observed, both at the cellular and organism levels. Epigenetics influence plethora of complications at cellular and molecular levels that includes cancer, metabolic and cardiovascular complications including neurological (psychosis) and neurodegenerative disorders (Alzheimer’s disease, Parkinson disease etc.). The epigenetic mechanisms include DNA methylation, histone modification and non coding RNA which have substantial impact on progression and pathways linked to Alzheimer’s disease. The epigenetic mechanism gets deregulated in Alzheimer’s disease and is characterized by DNA hyper methylation, deacetylation of histones and general repressed chromatin state which alter gene expression at the transcription level by upregulation, downregulation or silencing of genes. Thus, the processes or modulators of these epigenetic processes have shown vast potential as a therapeutic target in Alzheimer’s disease.
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Affiliation(s)
| | - Vineet Mehta
- Govt. College of Pharmacy, Rohru, District Shimla, Himachal Pradesh-171207, India
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Ubiquitin-conjugating enzyme E2T regulates cell proliferation and migration in cholangiocarcinoma. Anticancer Drugs 2021; 31:836-846. [PMID: 32796405 DOI: 10.1097/cad.0000000000000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Ubiquitin-conjugating enzyme E2T (UBE2T) is overexpressed in several human cancer cells, but a role in cholangiocarcinoma (CAA) progression has not been investigated. We analyzed the expression of UBE2T in CAA tissues. Then, we generated UBE2T deregulation models in which it was overexpressed or silenced, and examined the effects on CAA malignant progression by flow cytometry, western blot, MTT assay, wound healing assay and transwell assay. We report the involvement of UBE2T in CAA malignant progression. UBE2T was found to be highly expressed in human CAA cells both in vitro and in vivo. Overexpression of UBE2T significantly enhanced epithelial-to-mesenchymal transition, proliferation, migration and invasion of CAA cells in vitro, while silencing UBE2T had opposing effects. Furthermore, UBE2T appears to exert its effects via the mammalian target of rapamycin (mTOR) pathway as the cellular effects caused by UBE2T overexpression are inhibited by the mTOR inhibitor rapamycin. Our findings suggest that UBE2T may have potential as a new therapeutic target for the prevention or treatment of CAA.
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Wang R, Yao J, Gong F, Chen S, He Y, Hu C, Li C. miR-29c-3p regulates TET2 expression and inhibits autophagy process in Parkinson's disease models. Genes Cells 2021; 26:684-697. [PMID: 34086379 DOI: 10.1111/gtc.12877] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 05/31/2021] [Accepted: 06/01/2021] [Indexed: 12/15/2022]
Abstract
Autophagy in dopamine (DA) neurons is concerned to be associated with Parkinson's disease (PD), but the detailed mechanism remains unknown. Herein, we aimed to investigate the function of microRNA (miR)-29c-3p in autophagy in PD models. Intraperitoneal injection of MPTP (20 mg/kg) was given to C57BL/6 mice to establish PD mouse model. SH-SY5Y cells were treated with MPP+ (1 mmol/L) to establish in vitro PD model. The results indicated that in the substantia nigra pars compacta (SNpc) DA neurons of PD mice, autophagy was activated accompanied by down-regulated miR-29c-3p and up-regulated ten-eleven translocation 2 (TET2) expression. Up-regulation of miR-29c-3p inhibited TET2 expression and SNpc (including DA neurons) autophagy in PD mice. In vitro PD model confirmed that MPP+ treatment markedly down-regulated miR-29c-3p expression and up-regulated TET2 expression in SH-SY5Y cells in a dose/time-dependent manner. Moreover, miR-29c-3p up-regulation also inhibited autophagy and TET2 expression in vitro. Additionally, TET2 was proved to be targeted and down-regulated by miR-29c-3p. TET2 knockdown inhibited MPP+ -induced autophagy, whereas TET2 over-expression reversed the effects of miR-29c-3p over-expression on SH-SY5Y cell autophagy. Overall, miR-29c-3p over-expression inhibits autophagy in PD models, which may be mediated by TET2. Our finding may provide new insights for regulating autophagy to improve PD progression.
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Affiliation(s)
- Ruili Wang
- Department of Geriatric Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jie Yao
- Department of Geriatric Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Fuhua Gong
- Department of Geriatric Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Songsheng Chen
- Department of Geriatric Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ya He
- Department of Geriatric Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Chunting Hu
- Department of Geriatric Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Chen Li
- Department of Geriatric Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Coppedè F. Epigenetic regulation in Alzheimer's disease: is it a potential therapeutic target? Expert Opin Ther Targets 2021; 25:283-298. [PMID: 33843425 DOI: 10.1080/14728222.2021.1916469] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Introduction: Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. Changes in DNA methylation and post-translational modifications of histone tails are increasingly observed in AD tissues, and likely contribute to disease onset and progression. The reversibility of these epigenetic marks offers the potential for therapeutic interventions.Areas covered: After a concise and updated overview of DNA methylation and post-translational modifications of histone tails in AD tissues, this review provides an overview of the animal and cell culture studies investigating the potential of targeting these modifications to attenuate AD-like features. PubMed was searched for relevant literature between 2003 and 2021.Expert opinion: Methyl donor compounds and drugs acting on histone tail modifications attenuated the AD-like features and improved cognition in several transgenic AD mice; however, there are concerns about safety and tolerability for long-term treatment in humans. The challenges will be to take advantage of recent epigenome-wide investigations to identify the principal targets for future interventions, and to design novel, selective and safer agents. Natural compounds exerting epigenetic properties could represent a promising opportunity to delay disease onset in middle-aged individuals at increased AD risk.
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Affiliation(s)
- Fabio Coppedè
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy.,Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy
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Hajjari SN, Sadigh-Eteghad S, Shanehbandi D, Teimourian S, Shahbazi A, Mehdizadeh M. MicroRNA-4422-5p as a Negative Regulator of Amyloidogenic Secretases: A Potential Biomarker for Alzheimer's Disease. Neuroscience 2021; 463:108-115. [PMID: 33836245 DOI: 10.1016/j.neuroscience.2021.03.028] [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: 10/26/2020] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 10/21/2022]
Abstract
Beta-secretase (BACE1) and gamma-secretase activating protein (GSAP) are pivotal enzymes in the cleavage of amyloid precursor protein (APP). Beta-amyloid (Aß) formation is considered one of the main reasons for Alzheimer's disease (AD) pathology. In our preliminary study, a series of microRNAs (miRs) with possible interaction with BACE1 and/or GSAP was selected using computational analysis. Our results showed that miR-4422-5p had a reduced level in the serum of AD patients. In this study, the effect of miR-4422-5p using miR-4422-5p mimic and inhibitor on BACE1 and GSAP were investigated, and a probable novel early diagnostic marker for AD was introduced. The effect of miR-4422-5p interaction with BACE1 and GSAP was evaluated via in vitro experiments using dual-luciferase assays, western blotting, and Immunocytochemistry. Luciferase assay demonstrated that miR-4422-5p mimic suppresses BACE1 and GSAP expression by directly targeting the 3'UTR of BACE1 and GSAP mRNA in HEK293T cells. Also, western blotting and immunocytochemistry confirmed the regulatory role of miR-4422-5p mimic on BACE1 and GSAP genes. miR-4422-5p mimic significantly decreased BACE1 and GSAP protein expression in SH-SY5Y and A549 cells, respectively. Moreover, miR-4422-5p-inhibitor reversed the expression processes in both cell lines. Our data suggest that miR-4422-5p may be an important regulator of both BACE1 and GSAP genes and can represent a novel potential biomarker or therapeutic target in AD.
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Affiliation(s)
- Seyedeh Nazanin Hajjari
- Department of Neurosciences, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Teimourian
- Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Shahbazi
- Department of Neurosciences, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Mehdizadeh
- Cellular and Molecular Research Center, Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Moraghebi M, Maleki R, Ahmadi M, Negahi AA, Abbasi H, Mousavi P. In silico Analysis of Polymorphisms in microRNAs Deregulated in Alzheimer Disease. Front Neurosci 2021; 15:631852. [PMID: 33841080 PMCID: PMC8024493 DOI: 10.3389/fnins.2021.631852] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/18/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a degenerative condition characterized by progressive cognitive impairment and dementia. Findings have revolutionized current knowledge of miRNA in the neurological conditions. Two regulatory mechanisms determine the level of mature miRNA expression; one is miRNA precursor processing, and the other is gene expression regulation by transcription factors. This study is allocated to the in-silico investigation of miRNA's SNPs and their effect on other cell mechanisms. METHODS We used databases which annotate the functional effect of SNPs on mRNA-miRNA and miRNA-RBP interaction. Also, we investigated SNPs which are located on the promoter or UTR region. RESULTS miRNA SNP3.0 database indicated several SNPs in miR-339 and miR-34a in the upstream and downstream of pre-miRNA and mature miRNAs. While, for some miRNAs miR-124, and miR-125, no polymorphism was observed, and also miR-101 with ΔG -3.1 and mir-328 with ΔG 5.8 had the highest and lowest potencies to produce mature microRNA. SNP2TFBS web-server presented several SNPs which altered the Transcription Factor Binding Sites (TFBS) or generated novel TFBS in the promoter regions of related miRNA. At last, RBP-Var database provided a list of SNPs which alter miRNA-RBP interaction pattern and can also influence other miRNAs' expression. DISCUSSION The results indicated that SNPs microRNA affects both miRNA function and miRNA expression. Our study expands molecular insight into how SNPs in different parts of miRNA, including the regulatory (promoter), the precursor (pre-miRNA), functional regions (seed region of mature miRNA), and RBP-binding motifs, which theoretically may be correlated to the Alzheimer's disease.
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Affiliation(s)
- Mahta Moraghebi
- Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Reza Maleki
- Student Research Committee, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Ahmadi
- Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Ahmad Agha Negahi
- Department of Internal Medicine, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Hossein Abbasi
- Student Research Committee, Faculty of Para-Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Pegah Mousavi
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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Segaran RC, Chan LY, Wang H, Sethi G, Tang FR. Neuronal Development-Related miRNAs as Biomarkers for Alzheimer's Disease, Depression, Schizophrenia and Ionizing Radiation Exposure. Curr Med Chem 2021; 28:19-52. [PMID: 31965936 DOI: 10.2174/0929867327666200121122910] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 09/30/2019] [Accepted: 10/22/2019] [Indexed: 11/22/2022]
Abstract
Radiation exposure may induce Alzheimer's disease (AD), depression or schizophrenia. A number of experimental and clinical studies suggest the involvement of miRNA in the development of these diseases, and also in the neuropathological changes after brain radiation exposure. The current literature review indicated the involvement of 65 miRNAs in neuronal development in the brain. In the brain tissue, blood, or cerebral spinal fluid (CSF), 11, 55, or 28 miRNAs are involved in the development of AD respectively, 89, 50, 19 miRNAs in depression, and 102, 35, 8 miRNAs in schizophrenia. We compared miRNAs regulating neuronal development to those involved in the genesis of AD, depression and schizophrenia and also those driving radiation-induced brain neuropathological changes by reviewing the available data. We found that 3, 11, or 8 neuronal developmentrelated miRNAs from the brain tissue, 13, 16 or 14 miRNAs from the blood of patient with AD, depression and schizophrenia respectively were also involved in radiation-induced brain pathological changes, suggesting a possibly specific involvement of these miRNAs in radiation-induced development of AD, depression and schizophrenia respectively. On the other hand, we noted that radiationinduced changes of two miRNAs, i.e., miR-132, miR-29 in the brain tissue, three miRNAs, i.e., miR- 29c-5p, miR-106b-5p, miR-34a-5p in the blood were also involved in the development of AD, depression and schizophrenia, thereby suggesting that these miRNAs may be involved in the common brain neuropathological changes, such as impairment of neurogenesis and reduced learning memory ability observed in these three diseases and also after radiation exposure.
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Affiliation(s)
- Renu Chandra Segaran
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, Singapore 138602, Singapore
| | - Li Yun Chan
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, Singapore 138602, Singapore
| | - Hong Wang
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, Singapore 138602, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Feng Ru Tang
- Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, CREATE Tower, Singapore 138602, Singapore
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Nikolac Perkovic M, Videtic Paska A, Konjevod M, Kouter K, Svob Strac D, Nedic Erjavec G, Pivac N. Epigenetics of Alzheimer's Disease. Biomolecules 2021; 11:195. [PMID: 33573255 PMCID: PMC7911414 DOI: 10.3390/biom11020195] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/19/2021] [Accepted: 01/26/2021] [Indexed: 02/07/2023] Open
Abstract
There are currently no validated biomarkers which can be used to accurately diagnose Alzheimer's disease (AD) or to distinguish it from other dementia-causing neuropathologies. Moreover, to date, only symptomatic treatments exist for this progressive neurodegenerative disorder. In the search for new, more reliable biomarkers and potential therapeutic options, epigenetic modifications have emerged as important players in the pathogenesis of AD. The aim of the article was to provide a brief overview of the current knowledge regarding the role of epigenetics (including mitoepigenetics) in AD, and the possibility of applying these advances for future AD therapy. Extensive research has suggested an important role of DNA methylation and hydroxymethylation, histone posttranslational modifications, and non-coding RNA regulation (with the emphasis on microRNAs) in the course and development of AD. Recent studies also indicated mitochondrial DNA (mtDNA) as an interesting biomarker of AD, since dysfunctions in the mitochondria and lower mtDNA copy number have been associated with AD pathophysiology. The current evidence suggests that epigenetic changes can be successfully detected, not only in the central nervous system, but also in the cerebrospinal fluid and on the periphery, contributing further to their potential as both biomarkers and therapeutic targets in AD.
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Affiliation(s)
- Matea Nikolac Perkovic
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
| | - Alja Videtic Paska
- Medical Center for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (A.V.P.); (K.K.)
| | - Marcela Konjevod
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
| | - Katarina Kouter
- Medical Center for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia; (A.V.P.); (K.K.)
| | - Dubravka Svob Strac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
| | - Gordana Nedic Erjavec
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
| | - Nela Pivac
- Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Ruder Boskovic Institute, HR-10000 Zagreb, Croatia; (M.N.P.); (M.K.); (D.S.S.); (G.N.E.)
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Varma-Doyle AV, Lukiw WJ, Zhao Y, Lovera J, Devier D. A hypothesis-generating scoping review of miRs identified in both multiple sclerosis and dementia, their protein targets, and miR signaling pathways. J Neurol Sci 2021; 420:117202. [PMID: 33183778 DOI: 10.1016/j.jns.2020.117202] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 09/26/2020] [Accepted: 10/19/2020] [Indexed: 12/11/2022]
Abstract
Cognitive impairment (CI) is a frequent complication affecting people with multiple sclerosis (MS). The causes of CI in MS are not fully understood. Besides MRI measures, few other biomarkers exist to help us predict the development of CI and understand its biology. MicroRNAs (miRs) are relatively stable, non-coding RNA molecules about 22 nucleotides in length that can serve as biomarkers and possible therapeutic targets in several autoimmune and neurodegenerative diseases, including the dementias. In this review, we identify dysregulated miRs in MS that overlap with dysregulated miRs in cognitive disorders and dementia and explore how these overlapping miRs play a role in CI in MS. MiR-15, miR-21, miR-128, miR-132, miR-138, miR-142, miR-146a, miR-155, miR-181, miR-572, and let-7 are known to contribute to various forms of dementia and show abnormal expression in MS. These overlapping miRs are involved in pathways related to apoptosis, neuroinflammation, glutamate toxicity, astrocyte activation, microglial burst activity, synaptic dysfunction, and remyelination. The mechanisms of action suggest that these miRs may be related to CI in MS. From our review, we also delineated miRs that could be neuroprotective in MS, namely miR-23a, miR-219, miR-214, and miR-22. Further studies can help clarify if these miRs are responsible for CI in MS, leading to potential therapeutic targets.
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Affiliation(s)
- Aditi Vian Varma-Doyle
- Louisiana State University Health Sciences Center -New Orleans School of Medicine, Department of Neurology, New Orleans, United States of America
| | - Walter J Lukiw
- Louisiana State University Health Sciences Center -New Orleans School of Medicine, Department of Neurology, New Orleans, United States of America; Louisiana State University Health Sciences Center - New Orleans Neuroscience Center, United States of America; Louisiana State University Health Sciences Center - New Orleans Department of Ophthalmology, United States of America
| | - Yuhai Zhao
- Louisiana State University Health Sciences Center - New Orleans Department of Cell Biology and Anatomy, United States of America; Louisiana State University Health Sciences Center - New Orleans Neuroscience Center, United States of America
| | - Jesus Lovera
- Louisiana State University Health Sciences Center -New Orleans School of Medicine, Department of Neurology, New Orleans, United States of America.
| | - Deidre Devier
- Louisiana State University Health Sciences Center -New Orleans School of Medicine, Department of Neurology, New Orleans, United States of America; Louisiana State University Health Sciences Center - New Orleans Department of Cell Biology and Anatomy, United States of America.
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miR-16-5p and miR-19b-3p prevent amyloid β-induced injury by targeting BACE1 in SH-SY5Y cells. Neuroreport 2021; 31:205-212. [PMID: 31876684 DOI: 10.1097/wnr.0000000000001379] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Alzheimer's disease is the most common neurodegenerative disease, characterized by accumulation of amyloid β peptides. MicroRNAs have been identified as significant regulators and therapeutic targets of Alzheimer's disease. However, the roles of miR-16-5p and miR-19b-3p and their mechanisms in Alzheimer's disease progression remain largely unknown. MATERIALS AND METHODS Amyloid β-treated SH-SY5Y cells were used to study Alzheimer's disease progression in vitro. Transfection was conducted into SH-SY5Y cells using Lipofectamine 2000. The expression levels of miR-16-5p, miR-19b-3p and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) were measured by quantitative real-time PCR or western blot, respectively. Cell viability and apoptosis were detected in amyloid β-treated SH-SY5Y cells by MTT or flow cytometry, respectively. The interaction between BACE1 and miR-16-5p or miR-19b-3p was explored by luciferase reporter and RNA immunoprecipitation analyses. RESULTS The expression levels of miR-16-5p and miR-19b-3p were reduced but BACE1 protein expression was enhanced in SH-SY5Y cells after treatment of amyloid β. Overexpression of miR-16-5p or miR-19b-3p attenuated amyloid β-induced viability inhibition and apoptosis promotion in SH-SY5Y cells, while their knockdown exacerbated amyloid β-induced injury. BACE1 was confirmed as a target of miR-16-5p and miR-19b-3p and its overexpression aggravated amyloid β-induced loss of viability and production of apoptosis, while its depletion caused an opposite effect. Moreover, upregulation of BACE1 alleviated the regulatory effects of miR-16-5p and miR-19b-3p on amyloid β-induced injury. CONCLUSION MiR-16-5p and miR-19b-3p relieved amyloid β-induced injury by targeting BACE1 in SH-SY5Y cells, indicating miR-16-5p and miR-19b-3p as protective agents for treatment of Alzheimer's disease.
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Siedlecki-Wullich D, Miñano-Molina AJ, Rodríguez-Álvarez J. microRNAs as Early Biomarkers of Alzheimer's Disease: A Synaptic Perspective. Cells 2021; 10:113. [PMID: 33435363 PMCID: PMC7827653 DOI: 10.3390/cells10010113] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 01/04/2021] [Accepted: 01/07/2021] [Indexed: 02/07/2023] Open
Abstract
Pathogenic processes underlying Alzheimer's disease (AD) affect synaptic function from initial asymptomatic stages, long time before the onset of cognitive decline and neurodegeneration. Therefore, reliable biomarkers enabling early AD diagnosis and prognosis are needed to maximize the time window for therapeutic interventions. MicroRNAs (miRNAs) have recently emerged as promising cost-effective and non-invasive biomarkers for AD, since they can be readily detected in different biofluids, including cerebrospinal fluid (CSF) and blood. Moreover, a growing body of evidence indicates that miRNAs regulate synaptic homeostasis and plasticity processes, suggesting that they may be involved in early synaptic dysfunction during AD. Here, we review the current literature supporting a role of miRNAs during early synaptic deficits in AD, including recent studies evaluating their potential as AD biomarkers. Besides targeting genes related to Aβ and tau metabolism, several miRNAs also regulate synaptic-related proteins and transcription factors implicated in early synaptic deficits during AD. Furthermore, individual miRNAs and molecular signatures have been found to distinguish between prodromal AD and healthy controls. Overall, these studies highlight the relevance of considering synaptic-related miRNAs as potential biomarkers of early AD stages. However, further validation studies in large cohorts, including longitudinal studies, as well as implementation of standardized protocols, are needed to establish miRNA-based biomarkers as reliable diagnostic and prognostic tools.
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Affiliation(s)
- Dolores Siedlecki-Wullich
- Department Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain; (A.J.M.-M.); (J.R.-Á.)
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 528031 Madrid, Spain
| | - Alfredo J. Miñano-Molina
- Department Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain; (A.J.M.-M.); (J.R.-Á.)
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 528031 Madrid, Spain
| | - José Rodríguez-Álvarez
- Department Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain; (A.J.M.-M.); (J.R.-Á.)
- Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 528031 Madrid, Spain
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA
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Abstract
This paper was aimed to analyze the microRNA (miRNA) signatures in Alzheimer disease (AD) and find the significant expressions of miRNAs, their target genes, the functional enrichment analysis of the confirmed genes, and potential drug treatment. The miRNA expression information of the gene expression profile data was downloaded from the Gene Expression Omnibus database. The total data sample size is 1309, including 1021 AD samples and 288 normal samples. A total of 21 differentially expressed miRNAs were obtained, of which 16 (hsa-miR-6761-3p, hsa-miR-6747-3p, hsa-miR-6875-3p, hsa-miR-6754-3p, hsa-miR-6736-3p, hsa-miR-6762-3p, hsa-miR-6787-3p, hsa-miR-208a-5p, hsa-miR-6740-3p, hsa-miR-6778-3p, hsa-miR-595, hsa-miR-6753-3p, hsa-miR-4747-3p, hsa-miR-3646, hsa-miR-6716-3p and hsa-miR-4435) were up-regulated and 5 (hsa-miR-125a-3p, hsa-miR-22-3p, hsa-miR-24-3p, hsa-miR-6131 and hsa-miR-125b-1-3p) were down-regulated in AD. A total of 6 miRNAs (hsa-miR-595, hsa-miR-3646, hsa-miR-4435 hsa-miR-125a-3p, hsa-miR-22-3p and hsa-miR-24-3p) and 78 miRNA-disease-related gene sub-networks were predicted, and 116 ceRNA regulatory relationship pairs, and the ceRNA regulatory network were obtained. The results of enrichment analysis suggested that the main target pathways of several miRNAs differentially expressed in AD were mitogen-activated protein kinase signal pathway. According to the prediction results of Drug-Gene Interaction database 2.0, we obtained 53 pairs of drug-gene interaction, including 7 genes (PTGS2, EGFR, CALM1, PDE4D, FGFR2, HMGCR, cdk6) and 53 drugs. We hope our results are helpful to find a viable way to prevent, delay the onset, diagnose, and treat AD.
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Affiliation(s)
- Liu Lu
- Department of Neurology, The Affiliated WuXi No.2 People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Wen-Zhuo Dai
- Department of Neurology, The Affiliated WuXi No.2 People’s Hospital of Nanjing Medical University, Wuxi, China
| | - Xi-Chen Zhu
- Department of Neurology, The Affiliated WuXi No.2 People’s Hospital of Nanjing Medical University, Wuxi, China
- Department of Neurology, the WuXi NO.2 People’s Hospital, Affiliated Wuxi Clinical College of Nantong University, Wuxi, Jiangsu, China
| | - Tao Ma
- Department of Neurology, The Affiliated WuXi No.2 People’s Hospital of Nanjing Medical University, Wuxi, China
- Department of Neurology, the WuXi NO.2 People’s Hospital, Affiliated Wuxi Clinical College of Nantong University, Wuxi, Jiangsu, China
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Zhao S, Liu X, Kang J, Sun S, Li Y, Zhang J, Li Q, Ji X. Analysis of microRNA expression in cerebral ischemia/reperfusion after mild therapeutic hypothermia treatment in rats. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:168. [PMID: 33569470 PMCID: PMC7867934 DOI: 10.21037/atm-21-143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background This study aimed to explore the molecular mechanism of mild hypothermia in in the treatment of cerebral ischemia, microRNA (miRNA) microarrays and bioinformatics analysis were employed to examine the miRNA expression profiles of rats with mild therapeutic hypothermia after middle cerebral artery occlusion (MCAO). Methods MCAO was induced in Male Sprague–Dawley rats. Mild hypothermia treatment began from the onset of ischemia and maintained for 3 hours. miRNA expressions following focal cerebral ischemia and mild hypothermia treatment were profiled using microarray technology. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the functions of the target genes in mild therapeutic hypothermia after MCAO. 60 min before MCAO, mimics and inhibitor of miR-291b were injected into the right lateral ventricle respectively, then the infarct volume and neuronal apoptosis were analyzed. Results Six upregulated miRNAs and 6 downregulated miRNAs were detected 4 hours after mild therapeutic hypothermia, and after 24 hours, 41 and 10 miRNAs were upregulated and downregulated, respectively. The target genes of the differentially expressed genes were mainly related with multicellular organism development and the mucin type O-glycan biosynthesis pathway was the most enriched KEGG pathway. Among the differentially expressed miRNAs, miR-291b was selected to assess the effects of mild therapeutic hypothermia in MCAO rats. At 24 hours after mild therapeutic hypothermia, miR-291b overexpression was proved to exhibit neuroprotective effects. Conclusions The results showed that miRNAs might play a pivotal role in mild therapeutic hypothermia in cerebral ischemia/reperfusion injury. Further understanding of the mechanism and function of miRNAs would help to illuminate the mechanism of mild therapeutic hypothermia in cerebral ischemia/reperfusion injury.
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Affiliation(s)
- Shangfeng Zhao
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Xiangrong Liu
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Jun Kang
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Si Sun
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yong Li
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jialiang Zhang
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Qi Li
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xunming Ji
- Department of Neurosurgery, Xuanwu Hospital of Capital Medical University, Beijing, China
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Tecalco-Cruz AC, Ramírez-Jarquín JO, Alvarez-Sánchez ME, Zepeda-Cervantes J. Epigenetic basis of Alzheimer disease. World J Biol Chem 2020; 11:62-75. [PMID: 33024518 PMCID: PMC7520642 DOI: 10.4331/wjbc.v11.i2.62] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/30/2020] [Accepted: 09/10/2020] [Indexed: 02/05/2023] Open
Abstract
Alzheimer disease (AD) is the primary form of dementia that occurs spontaneously in older adults. Interestingly, the epigenetic profile of the cells forming the central nervous system changes during aging and may contribute to the progression of some neurodegenerative diseases such as AD. In this review, we present general insights into relevant epigenetic mechanisms and their relationship with aging and AD. The data suggest that some epigenetic changes during aging could be utilized as biomarkers and target molecules for the prevention and control of AD.
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Affiliation(s)
- Angeles C Tecalco-Cruz
- Programa en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico 03100, Mexico
| | - Josué O Ramírez-Jarquín
- División de neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico 04510, Mexico
| | | | - Jesus Zepeda-Cervantes
- Biología celular y de desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico 04510, Mexico
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MicroRNAs Modulate the Pathogenesis of Alzheimer's Disease: An In Silico Analysis in the Human Brain. Genes (Basel) 2020; 11:genes11090983. [PMID: 32846925 PMCID: PMC7564652 DOI: 10.3390/genes11090983] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/07/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are small RNAs involved in the post-transcriptional regulation of their target genes, causing a decrease in protein translation from the mRNA. Different miRNAs are found in the nervous system, where they are involved in its physiological functions, but altered miRNAs expression was also reported in neurodegenerative disorders, including Alzheimer's disease (AD). AD is characterized by memory loss, cognitive function abnormalities, and various neuropsychiatric disturbances. AD hallmarks are amyloid β (Aβ) aggregates, called senile plaques, and neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau protein. In this study, we performed an in silico analysis to evaluate altered patterns of miRNAs expression in the brains of AD patients compared to healthy subjects. We found 12 miRNAs that were differentially expressed in AD compared to healthy individuals. These miRNAs have target genes involved in AD pathogenesis. In particular, some miRNAs influence Aβ production, having as target secretase and amyloid precursor protein (APP). Some miRNAs were reported to be involved in nervous system functions, and their alteration can cause neuronal dysfunction.
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Wei W, Wang ZY, Ma LN, Zhang TT, Cao Y, Li H. MicroRNAs in Alzheimer's Disease: Function and Potential Applications as Diagnostic Biomarkers. Front Mol Neurosci 2020; 13:160. [PMID: 32973449 PMCID: PMC7471745 DOI: 10.3389/fnmol.2020.00160] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/05/2020] [Indexed: 12/14/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common form of dementia. Although the incidence of AD is high, the rates of diagnosis and treatment are relatively low. Moreover, effective means for the diagnosis and treatment of AD are still lacking. MicroRNAs (miRNAs, miRs) are non-coding RNAs that play regulatory roles by targeting mRNAs. The expression of miRNAs is conserved, temporal, and tissue-specific. Impairment of microRNA function is closely related to AD pathogenesis, including the beta-amyloid and tau hallmarks of AD, and there is evidence that the expression of some microRNAs differs significantly between healthy people and AD patients. These properties of miRNAs endow them with potential diagnostic and therapeutic value in the treatment of this debilitating disease. This review provides comprehensive information about the regulatory function of miRNAs in AD, as well as potential applications as diagnostic biomarkers.
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Affiliation(s)
- Wei Wei
- First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, China.,Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhi-Yong Wang
- Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li-Na Ma
- Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ting-Ting Zhang
- First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, China.,Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yu Cao
- Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hao Li
- Department of Geriatrics, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Ha L, Yang B, Wang S, An Y, Wang H, Cui Y. Effect of Moxibustion on Behavioral Changes and Expression of APP and BACE1 in Hippocampus of SAMP8 Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:3598930. [PMID: 32855649 PMCID: PMC7443240 DOI: 10.1155/2020/3598930] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/14/2020] [Accepted: 07/07/2020] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To observe the effect of moxibustion on cognitive function of aging mice, to observe the effect of moxibustion on protein and gene expression of APP metabolism pathway, and to explore the mechanism of action in moxibustion. METHODS 24 SAMP8 were randomly divided into 2 groups (12 in each group): moxibustion group and model group. 12 SAMR1 mice were used as blank controls. Mice in the moxibustion group were treated with moxibustion for 8 weeks, 10 minutes each time, 5 times a week, and for a total of 8 weeks. The model group and the blank group were treated with sham-moxibustion. Behavior tests were used to detect the learning and memory ability of each group of mice. Immunohistochemical, western blot, and RT-PCR were used to detect the protein and mRNA expression of APP and BACE1. Furthermore, the expressions of miR-29 and miR-101 were observed by RT-PCR method to explore the mechanism of moxibustion at the genetic level. RESULTS In this study, relative to normal mice, we found that aging mice showed behavioral changes consistent with the onset of AD. However, moxibustion interventions were able to mitigate these effects to some degree in aging mice. In addition, moxibustion was proved to regulate APP metabolism pathway at protein and gene level through molecular biology tests. CONCLUSION The data suggest that the effect of moxibustion intervention on cognitive function in aging mice is related to the regulation of genes and proteins involved in APP metabolism pathway; this may be a potential target for treating Alzheimer's disease.
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Affiliation(s)
- Lue Ha
- School of Acupuncture, Moxibustion and Massage, Shaanxi University of Chinese Medicine, Xixian New Area, Xianyang 712046, China
| | - Bin Yang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Shaosong Wang
- Beijing TCM Hospital Affiliated to Capital Medical University, Beijing 100029, China
| | - Yu An
- School of Acupuncture, Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hao Wang
- School of Acupuncture, Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Yingxue Cui
- Beijing TCM Hospital Affiliated to Capital Medical University, Beijing 100029, China
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Improta-Caria AC, Nonaka CKV, Cavalcante BRR, De Sousa RAL, Aras Júnior R, Souza BSDF. Modulation of MicroRNAs as a Potential Molecular Mechanism Involved in the Beneficial Actions of Physical Exercise in Alzheimer Disease. Int J Mol Sci 2020; 21:E4977. [PMID: 32674523 PMCID: PMC7403962 DOI: 10.3390/ijms21144977] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/23/2020] [Accepted: 06/23/2020] [Indexed: 12/18/2022] Open
Abstract
Alzheimer disease (AD) is one of the most common neurodegenerative diseases, affecting middle-aged and elderly individuals worldwide. AD pathophysiology involves the accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain, along with chronic neuroinflammation and neurodegeneration. Physical exercise (PE) is a beneficial non-pharmacological strategy and has been described as an ally to combat cognitive decline in individuals with AD. However, the molecular mechanisms that govern the beneficial adaptations induced by PE in AD are not fully elucidated. MicroRNAs are small non-coding RNAs involved in the post-transcriptional regulation of gene expression, inhibiting or degrading their target mRNAs. MicroRNAs are involved in physiological processes that govern normal brain function and deregulated microRNA profiles are associated with the development and progression of AD. It is also known that PE changes microRNA expression profile in the circulation and in target tissues and organs. Thus, this review aimed to identify the role of deregulated microRNAs in the pathophysiology of AD and explore the possible role of the modulation of microRNAs as a molecular mechanism involved in the beneficial actions of PE in AD.
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Affiliation(s)
- Alex Cleber Improta-Caria
- Post-Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Bahia 40110-909, Brazil; (A.C.I.-C.); (R.A.J.)
- University Hospital Professor Edgard Santos, Bahia 40110-909, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Bahia 40110-909, Brazil; (C.K.V.N.); (B.R.R.C.)
| | - Carolina Kymie Vasques Nonaka
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Bahia 40110-909, Brazil; (C.K.V.N.); (B.R.R.C.)
- D’Or Institute for Research and Education (IDOR), Rio de Janeiro 20000-000, Brazil
| | - Bruno Raphael Ribeiro Cavalcante
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Bahia 40110-909, Brazil; (C.K.V.N.); (B.R.R.C.)
- D’Or Institute for Research and Education (IDOR), Rio de Janeiro 20000-000, Brazil
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Bahia 40110-909, Brazil
| | - Ricardo Augusto Leoni De Sousa
- Physiological Science Multicentric Program, Federal University of Valleys´ Jequitinhonha and Mucuri, Minas Gerais 30000-000, Brazil;
| | - Roque Aras Júnior
- Post-Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Bahia 40110-909, Brazil; (A.C.I.-C.); (R.A.J.)
- University Hospital Professor Edgard Santos, Bahia 40110-909, Brazil
| | - Bruno Solano de Freitas Souza
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Bahia 40110-909, Brazil; (C.K.V.N.); (B.R.R.C.)
- D’Or Institute for Research and Education (IDOR), Rio de Janeiro 20000-000, Brazil
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Bahia 40110-909, Brazil
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Han L, Tang Y, Bai X, Liang X, Fan Y, Shen Y, Huang F, Wang J. Association of the serum microRNA-29 family with cognitive impairment in Parkinson's disease. Aging (Albany NY) 2020; 12:13518-13528. [PMID: 32649312 PMCID: PMC7377865 DOI: 10.18632/aging.103458] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/27/2020] [Indexed: 04/19/2023]
Abstract
We aimed to examine whether miRNA-29s (miR-29s) in serum are associated with cognitive impairment in Parkinson's disease (PD). Thirty-nine PD patients with normal cognition (PD-NC), 37 PD patients with mild cognitive impairment (PD-MCI), 22 PD patients with dementia (PDD) and 40 healthy controls were recruited. Detailed clinical evaluations and a schedule of neuropsychological tests were administered to all patients. MiR-29s expression in serum samples was assessed using reverse-transcription quantitative real-time PCR. We found that the levels of all three miR-29s in the PDD group were significantly lower than those in the PD-NC group (p < 0.05). In addition, the miR-29b level was downregulated in the PD-MCI group with respect to that in the PD-NC group (p < 0.05). After adjusting for years of education and the UPDRS-III subscore using a multivariate model, miR-29s showed significant associations with PDD. MiR-29b levels were shown to be associated with different subsets of PD cognition and could accurately discriminate PDD from non-PDD (area under the curve (AUC) = 0.859; 95% CI, 0.7817-0.9372). Further analysis of the cognitive domains found that the miR-29s levels were all associated with memory performance in PD patients. In summary, miR-29s are associated with cognitive impairment in PD.
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Affiliation(s)
- Linlin Han
- Department of Neurology and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yilin Tang
- Department of Neurology and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Xiaochen Bai
- Department of Neurology and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Xiaoniu Liang
- Department of Neurology and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yun Fan
- Department of Neurology and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yan Shen
- Department of Neurology and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Fang Huang
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Jian Wang
- Department of Neurology and National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
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Jahangard Y, Monfared H, Moradi A, Zare M, Mirnajafi-Zadeh J, Mowla SJ. Therapeutic Effects of Transplanted Exosomes Containing miR-29b to a Rat Model of Alzheimer's Disease. Front Neurosci 2020; 14:564. [PMID: 32625049 PMCID: PMC7314926 DOI: 10.3389/fnins.2020.00564] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/07/2020] [Indexed: 12/16/2022] Open
Abstract
Alzheimer disease (AD) is a complex neurodegenerative disorder with no definite treatment. The expression of miR-29 family is significantly reduced in AD, suggesting a part for the family members in pathogenesis of the disease. The recent emergence of microRNA (miRNA)-based therapeutic approaches is emphasized on the efficiency of miRNA transfer to target cells. The endogenously made secretory vesicles could provide a biological vehicle for drug delivery. Characteristics such as small sizes, the ability to cross the blood-brain barrier, the specificity in binding to the right target cells, and most importantly the capacity to be engineered as drug carriers have made exosomes desirable vehicles to deliver genetic materials to the central nervous system. Here, we transfected rat bone marrow mesenchymal stem cells and HEK-293T cells (human embryonic kidney 293 cells) with recombinant expression vectors, carrying either mir-29a or mir-29b precursor sequences. A significant overexpression of miR-29 and downregulation of their targets genes, BACE1 (β-site amyloid precursor protein cleaving enzyme 1) and BIM [Bcl-2 interacting mediator of cell death (BCL2-like 11)], were confirmed in the transfected cells. Then, we confirmed the packaging of miR-29 in exosomes secreted from the transfected cells. Finally, we investigated a possible therapeutic effect of the engineered exosomes to reduce the pathological effects of amyloid-β (Aβ) peptide in a rat model of AD. Aβ-treated model rats showed some deficits in spatial learning and memory. However, in animals injected with miR-29-containing exosomes at CA1 (cornu ammonis area), the aforementioned impairments were prevented. In conclusion, our findings provide a new approach for the packaging of miR-29 in exosomes and that the engineered exosomes might have a therapeutic potential in AD.
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Affiliation(s)
- Yavar Jahangard
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hamideh Monfared
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arman Moradi
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Meysam Zare
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Javad Mirnajafi-Zadeh
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Javad Mowla
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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