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1
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Gupta A, Ghosh A, Sharma N, Gorain B. Advancements in Stem Cell Research for Effective Therapies Against Alzheimer's Disease: Current Investigation and Future Insight. Mol Neurobiol 2025:10.1007/s12035-025-05003-3. [PMID: 40327307 DOI: 10.1007/s12035-025-05003-3] [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: 09/29/2024] [Accepted: 04/25/2025] [Indexed: 05/07/2025]
Abstract
Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly, affecting approximately 50 million individuals globally with significant impose in health and financial burdens. Despite extensive research, no current treatment effectively halts the progression of AD, primarily due to its complex pathophysiology of the disease and the limitations of available therapeutic approaches. In this context, stem cell transplantation has emerged as a promising treatment strategy, harnessing the regenerative capabilities of various stem cell types, including neural stem cells (NSCs), embryonic stem cells (ESCs), and mesenchymal stem cells (MSCs). This review explores the potential of stem cell-based therapies in AD, emphasizing the necessity for continued innovation to overcome existing challenges and enhance therapeutic efficacy. Briefly, NSCs have shown potential in improving cognitive function and reducing AD pathology through targeted transplantation and neuroprotection; however, challenges such as optimizing transplantation protocols and ensuring effective cell integration persist. Concurrently, ESCs, with their pluripotent nature, present opportunities for modulating AD and generating therapeutic neurons, but ethical concerns and immunogenicity present significant obstacles to clinical application. Moreover, MSCs have demonstrated potential in ameliorating AD-related pathology and promoting neurogenesis, offering a more accessible alternative with fewer ethical constraints. The review concludes that the combinatory approaches of different stem cells may provide synergistic benefits in addressing AD-related pathophysiology, warranting further exploration in future research.
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Affiliation(s)
- Abhinav Gupta
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Arya Ghosh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Neelima Sharma
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
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2
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Pan Y, Li L, Cao N, Liao J, Chen H, Zhang M. Advanced nano delivery system for stem cell therapy for Alzheimer's disease. Biomaterials 2025; 314:122852. [PMID: 39357149 DOI: 10.1016/j.biomaterials.2024.122852] [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: 06/20/2024] [Revised: 09/10/2024] [Accepted: 09/26/2024] [Indexed: 10/04/2024]
Abstract
Alzheimer's Disease (AD) represents one of the most significant neurodegenerative challenges of our time, with its increasing prevalence and the lack of curative treatments underscoring an urgent need for innovative therapeutic strategies. Stem cells (SCs) therapy emerges as a promising frontier, offering potential mechanisms for neuroregeneration, neuroprotection, and disease modification in AD. This article provides a comprehensive overview of the current landscape and future directions of stem cell therapy in AD treatment, addressing key aspects such as stem cell migration, differentiation, paracrine effects, and mitochondrial translocation. Despite the promising therapeutic mechanisms of SCs, translating these findings into clinical applications faces substantial hurdles, including production scalability, quality control, ethical concerns, immunogenicity, and regulatory challenges. Furthermore, we delve into emerging trends in stem cell modification and application, highlighting the roles of genetic engineering, biomaterials, and advanced delivery systems. Potential solutions to overcome translational barriers are discussed, emphasizing the importance of interdisciplinary collaboration, regulatory harmonization, and adaptive clinical trial designs. The article concludes with reflections on the future of stem cell therapy in AD, balancing optimism with a pragmatic recognition of the challenges ahead. As we navigate these complexities, the ultimate goal remains to translate stem cell research into safe, effective, and accessible treatments for AD, heralding a new era in the fight against this devastating disease.
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Affiliation(s)
- Yilong Pan
- Department of Cardiology, Shengjing Hospital of China Medical University, Liaoning, 110004, China.
| | - Long Li
- Department of Neurosurgery, First Hospital of China Medical University, Liaoning, 110001, China.
| | - Ning Cao
- Army Medical University, Chongqing, 400000, China
| | - Jun Liao
- Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
| | - Huiyue Chen
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Liaoning, 110001, China.
| | - Meng Zhang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Liaoning, 110004, China.
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3
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Kaur K, Narang RK, Singh S. Role of Nrf2 in Oxidative Stress, Neuroinflammation and Autophagy in Alzheimer's Disease: Regulation of Nrf2 by Different Signaling Pathways. Curr Mol Med 2025; 25:372-387. [PMID: 37493162 DOI: 10.2174/1566524023666230726145447] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 07/27/2023]
Abstract
Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the leading cause of dementia. AD is characterized by the aggregation of amyloid-ß (Aß) peptide, increased levels of tau protein, and loss of redox homeostasis responsible for mitochondrial dysfunction, oxidative stress, and neuroinflammation. Excessive accumulation of toxic Aß plaques activates microglia, which initiates neuroinflammation and consequently accelerates synaptic damage and neuronal loss. Various proinflammatory cytokines release, microglia proliferation, reactive astrocyte, and oxidative (reactive oxygen species (ROS) production, level of antioxidant enzymes, redox homeostasis, and lipid peroxidation) stress play a major role in AD. Several studies revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox homeostasis and works as an anti-inflammatory in various neurodegenerative disorders. D-Glutamate expression of transcription factor Nrf2 and its genes (glutamate-cysteine ligase catalytic subunit (GCLC), Heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase I (NQO1)) has been found in AD. Nrf2-HO-1 enhances the expression of antioxidant genes, inhibits microglia-mediated inflammation, and boosts mitochondrial function, suggesting that modulators of this protein may be useful to manage AD. This review focuses on the role of Nrf2 in AD, with a particular emphasis on the various pathways involved in the positive and negative modulation of Nrf2, namely Phosphoinositide 3-kinase (PI3K), Glycogen synthase kinase-3 (GSK-3), Nuclear factor kappa-B (NF-κB), and p38Mitogen-activated protein kinases (p38MAPK). Also, we have discussed the progress and challenges regarding the Nrf2 activators for AD treatment.
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Affiliation(s)
- Karamjeet Kaur
- Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India affiliated to IKG- Punjab Technical University, Jalandhar Punjab, 144603, India
| | - Raj Kumar Narang
- Nanomedicine Research Centre, Department of Pharmaceutics, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Shamsher Singh
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India
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Lee GB, Park SM, Jung UJ, Kim SR. The Potential of Mesenchymal Stem Cells in Treating Spinocerebellar Ataxia: Advances and Future Directions. Biomedicines 2024; 12:2507. [PMID: 39595073 PMCID: PMC11591855 DOI: 10.3390/biomedicines12112507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/28/2024] [Accepted: 10/31/2024] [Indexed: 11/28/2024] Open
Abstract
Spinocerebellar ataxia (SCA) is a heterogeneous disorder characterized by impaired balance and coordination caused by cerebellar dysfunction. The absence of treatments approved by the U.S. Food and Drug Administration for SCA has driven the investigation of alternative therapeutic strategies, including stem cell therapy. Mesenchymal stem cells (MSCs), known for their multipotent capabilities, have demonstrated significant potential in treating SCA. This review examines how MSCs may promote neuronal growth, enhance synaptic connectivity, and modulate brain inflammation. Recent findings from preclinical and clinical studies are also reviewed, emphasizing the promise of MSC therapy in addressing the unmet needs of SCA patients. Furthermore, ongoing clinical trials and future directions are proposed to address the limitations of the current approaches.
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Affiliation(s)
- Gi Beom Lee
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; (G.B.L.); (S.M.P.)
| | - Se Min Park
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; (G.B.L.); (S.M.P.)
| | - Un Ju Jung
- Department of Food Science and Nutrition, Pukyong National University, Busan 48513, Republic of Korea;
| | - Sang Ryong Kim
- School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; (G.B.L.); (S.M.P.)
- Brain Science and Engineering Institute, Kyungpook National University, Daegu 41404, Republic of Korea
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Bhatt A, Bhardwaj H, Srivastava P. Mesenchymal stem cell therapy for Alzheimer's disease: A novel therapeutic approach for neurodegenerative diseases. Neuroscience 2024; 555:52-68. [PMID: 39032806 DOI: 10.1016/j.neuroscience.2024.07.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/23/2024]
Abstract
Alzheimer's disease (AD) is one of the most progressive and prevalent types of neurodegenerative diseases in the aging population (aged >65 years) and is considered a major factor for dementia, affecting 55 million people worldwide. In the current scenario, drug-based therapies have been employed for the treatment of Alzheimer's disease but are only able to provide symptomatic relief to patients rather than a permanent solution from Alzheimer's. Recent advancements in stem cell research unlock new horizons for developing effective and highly potential therapeutic approaches due to their self-renewal, self-replicating, regenerative, and high differentiation capabilities. Stem cells come in multiple lineages such as embryonic, neural, and induced pluripotent, among others. Among different kinds of stem cells, mesenchymal stem cells are the most investigated for Alzheimer's treatment due to their multipotent nature, low immunogenicity, ability to penetrate the blood-brain barrier, and low risk of tumorigenesis, immune & inflammatory modulation, etc. They have been seen to substantially promote neurogenesis, synaptogenesis by secreting neurotrophic growth factors, as well as in ameliorating the Aβ and tau-mediated toxicity. This review covers the pathophysiology of AD, new medications, and therapies. Further, it will focus on the advancements and benefits of Mesenchymal Stem Cell therapies, their administration methods, clinical trials concerning AD progression, along with their future prospective.
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Affiliation(s)
- Aditya Bhatt
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Harshita Bhardwaj
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Priyanka Srivastava
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India.
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Rahimi Darehbagh R, Seyedoshohadaei SA, Ramezani R, Rezaei N. Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives. Eur J Med Res 2024; 29:386. [PMID: 39054501 PMCID: PMC11270957 DOI: 10.1186/s40001-024-01987-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 07/17/2024] [Indexed: 07/27/2024] Open
Abstract
Stem cell-based therapies have emerged as a promising approach for treating various neurological disorders by harnessing the regenerative potential of stem cells to restore damaged neural tissue and circuitry. This comprehensive review provides an in-depth analysis of the current state of stem cell applications in primary neurological conditions, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other related disorders. The review begins with a detailed introduction to stem cell biology, discussing the types, sources, and mechanisms of action of stem cells in neurological therapies. It then critically examines the preclinical evidence from animal models and early human trials investigating the safety, feasibility, and efficacy of different stem cell types, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs). While ESCs have been studied extensively in preclinical models, clinical trials have primarily focused on adult stem cells such as MSCs and NSCs, as well as iPSCs and their derivatives. We critically assess the current state of research for each cell type, highlighting their potential applications and limitations in different neurological conditions. The review synthesizes key findings from recent, high-quality studies for each neurological condition, discussing cell manufacturing, delivery methods, and therapeutic outcomes. While the potential of stem cells to replace lost neurons and directly reconstruct neural circuits is highlighted, the review emphasizes the critical role of paracrine and immunomodulatory mechanisms in mediating the therapeutic effects of stem cells in most neurological disorders. The article also explores the challenges and limitations associated with translating stem cell therapies into clinical practice, including issues related to cell sourcing, scalability, safety, and regulatory considerations. Furthermore, it discusses future directions and opportunities for advancing stem cell-based treatments, such as gene editing, biomaterials, personalized iPSC-derived therapies, and novel delivery strategies. The review concludes by emphasizing the transformative potential of stem cell therapies in revolutionizing the treatment of neurological disorders while acknowledging the need for rigorous clinical trials, standardized protocols, and multidisciplinary collaboration to realize their full therapeutic promise.
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Affiliation(s)
- Ramyar Rahimi Darehbagh
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Nanoclub Elites Association, Tehran, Iran
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
- Universal Scientific Education and Research Network (USERN), Sanandaj, Kurdistan, Iran
| | | | - Rojin Ramezani
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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7
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Liu Y, Xia X, Zheng M, Shi B. Bio-Nano Toolbox for Precision Alzheimer's Disease Gene Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2314354. [PMID: 38778446 DOI: 10.1002/adma.202314354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 05/01/2024] [Indexed: 05/25/2024]
Abstract
Alzheimer's disease (AD) is the most burdensome aging-associated neurodegenerative disorder, and its treatment encounters numerous failures during drug development. Although there are newly approved in-market β-amyloid targeting antibody solutions, pathological heterogeneity among patient populations still challenges the treatment outcome. Emerging advances in gene therapies offer opportunities for more precise personalized medicine; while, major obstacles including the pathological heterogeneity among patient populations, the puzzled mechanism for druggable target development, and the precision delivery of functional therapeutic elements across the blood-brain barrier remain and limit the use of gene therapy for central neuronal diseases. Aiming for "precision delivery" challenges, nanomedicine provides versatile platforms that may overcome the targeted delivery challenges for AD gene therapy. In this perspective, to picture a toolbox for AD gene therapy strategy development, the most recent advances from benchtop to clinics are highlighted, possibly available gene therapy targets, tools, and delivery platforms are outlined, their challenges as well as rational design elements are addressed, and perspectives in this promising research field are discussed.
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Affiliation(s)
- Yang Liu
- Department of Radiotherapy and Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng, Henan, 475000, China
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Xue Xia
- Department of Radiotherapy and Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng, Henan, 475000, China
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
- Macquarie Medical School, Faculty of Medicine & Health Sciences, Macquarie University, Sydney, New South Wales, 2109, Australia
| | - Meng Zheng
- Department of Radiotherapy and Translational Medicine Center, Huaihe Hospital of Henan University, Henan University, Kaifeng, Henan, 475000, China
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
| | - Bingyang Shi
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China
- Macquarie Medical School, Faculty of Medicine & Health Sciences, Macquarie University, Sydney, New South Wales, 2109, Australia
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Ataei B, Hokmabadi M, Asadi S, Asadifard E, Aghaei Zarch SM, Najafi S, Bagheri-Mohammadi S. A review of the advances, insights, and prospects of gene therapy for Alzheimer's disease: A novel target for therapeutic medicine. Gene 2024; 912:148368. [PMID: 38485038 DOI: 10.1016/j.gene.2024.148368] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 02/24/2024] [Accepted: 03/11/2024] [Indexed: 03/18/2024]
Abstract
Neurodegenerative diseases such as Alzheimer's disease (AD) are still an important issue for scientists because it is difficult to cure with the available molecular medications and conventional treatments. Due to the complex nature of the brain structures and heterogeneous morphological and physiological properties of neuronal cells, interventions for cerebral-related disorders using surgical approaches, and classical and ongoing treatments remain hard for physicians. Furthermore, the development of newly designed medications attempts to target AD are not successful in improving AD, because abnormalities of tau protein, aggregation of amyloid β (Aβ) peptide, inflammatory responses, etc lead to advanced neurodegeneration processes that conventional treatments cannot stop them. In recent years, novel diagnostic strategies and therapeutic approaches have been developed to identify and cure early pathological events of AD. Accordingly, many gene-based therapies have been developed and introduce the therapeutic potential to prevent and cure AD. On the other hand, genetic investigations and postmortem assessments have detected a large number of factors associated with AD pathology. Also, genetically diverse animal models of AD help us to detect and prioritize novel resilience mechanisms. Hence, gene therapy can be considered an effective and powerful tool to identify and treat human diseases. Ultimately, gene study and gene-based therapy with a critical role in the detection and cure of various human disorders will have a fundamental role in our lives forever. This scientific review paper discusses the present status of different therapeutic strategies, particularly gene-based therapy in treating AD, along with its challenges.
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Affiliation(s)
- Bahar Ataei
- Department of Genetics, Faculty of Basic Science, Shahrekord University, Shahrekord, Iran
| | - Mahsa Hokmabadi
- Department of Molecular Diagnosis, Armin Pathobiology and Medical Genetics Laboratory, Tehran, Iran; Medical Genomics Research Center, Tehran Medical Sciences Islamic Azad University, Tehran, Iran
| | - Sahar Asadi
- Department of Community and Family Medicine, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Elnaz Asadifard
- Medical Genomics Research Center, Tehran Medical Sciences Islamic Azad University, Tehran, Iran
| | - Seyed Mohsen Aghaei Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Saeid Bagheri-Mohammadi
- Department of Paramedicine, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran; Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
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Ahmad F, Karan A, Sharma R, Sharma NS, Sundar V, Jayaraj R, Mukherjee S, DeCoster MA. Evolving therapeutic interventions for the management and treatment of Alzheimer's disease. Ageing Res Rev 2024; 95:102229. [PMID: 38364913 DOI: 10.1016/j.arr.2024.102229] [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: 09/17/2023] [Revised: 12/11/2023] [Accepted: 02/10/2024] [Indexed: 02/18/2024]
Abstract
Alzheimer's Disease (AD) patients experience diverse symptoms, including memory loss, cognitive impairment, behavioral abnormalities, mood changes, and mental issues. The fundamental objective of this review is to discuss novel therapeutic approaches, with special emphasis on recently approved marketed formulations for the treatment of AD, especially Aducanumab, the first FDA approved moiety that surpasses the blood-brain barrier (BBB) and reduces amyloid plaques in the brain, thereby reducing associated cognitive decline. However, it is still in the phase IV trial and is to be completed by 2030. Other drugs such as lecanemab are also under clinical trial and has recently been approved by the FDA and is also discussed here. In this review, we also focus on active and passive immunotherapy for AD as well as several vaccines, such as amyloid-beta epitope-based vaccines, amyloid-beta DNA vaccines, and stem cell therapy for AD, which are in clinical trials. Furthermore, ongoing pre-clinical trials associated with AD and other novel strategies such as curcumin-loaded nanoparticles, Crispr/ cas9, precision medicine, as well as some emerging therapies like anti-sense therapy are also highlighted. Additionally, we discuss some off-labeled drugs like non-steroidal anti-inflammatory drugs (NSAID), anti-diabetic drugs, and lithium, which can manage symptoms of AD and different non-pharmacological approaches are also covered which can help to manage AD. In summary, we have tried to cover all the therapeutic interventions which are available for the treatment and management of AD under sections approved, clinical phase, pre-clinical phase or futuristic interventions, off-labelled drugs, and non-pharmacological interventions for AD, offering positive findings and well as challenges that remain.
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Affiliation(s)
- Faizan Ahmad
- Department of Medical Elementology and Toxicology, Jamia Hamdard University, Delhi, India
| | - Anik Karan
- Department of Mechanical and Bioengineering, University of Kansas, Lawrence, KS, USA.
| | - Rashi Sharma
- Department of Biotechnology, Delhi Technological University, Bawana, Delhi, India
| | - Navatha Shree Sharma
- Department of Surgery Transplant, University of Nebraska Medical Centre, Omaha, NE, USA
| | - Vaishnavi Sundar
- Department of Internal Medicine, University of Nebraska Medical Centre, Omaha, NE, USA
| | - Richard Jayaraj
- Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE
| | - Sudip Mukherjee
- Biomedical Engineering, Indian Institute of Technology- Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Mark A DeCoster
- Cellular Neuroscience Laboratory, Biomedical Engineering, College of Engineering and Science, Louisiana Tech University, Ruston, LA, USA; Cellular Neuroscience Laboratory, Institute for Micromanufacturing, College of Engineering and Science, Louisiana Tech University, Ruston, LA, USA.
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10
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Shen Z, Yang X, Lan Y, Chen G. The Neuro-Inflammatory Microenvironment: An Important Regulator of Stem Cell Survival in Alzheimer's Disease. J Alzheimers Dis 2024; 98:741-754. [PMID: 38489182 DOI: 10.3233/jad-231159] [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: 03/17/2024]
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive memory loss and cognitive impairment due to excessive accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. Although decades of research efforts have been put into developing disease-modifying therapies for AD, no "curative" drug has been identified. As a central player in neuro-inflammation, microglia play a key role inbrain homeostasis by phagocytosing debris and regulating the balance between neurotoxic and neuroprotective events. Typically, the neurotoxic phenotype of activated microglia is predominant in the impaired microenvironment of AD. Accordingly, transitioning the activity state of microglia from pro-inflammatory to anti-inflammatory can restore the disrupted homeostatic microenvironment. Recently, stem cell therapy holds great promise as a treatment for AD; however, the diminished survival of transplanted stem cells has resulted in a disappointing long-term outcome for this treatment. This article reviews the functional changes of microglia through the course of AD-associated homeostatic deterioration. We summarize the possible microglia-associated therapeutic targets including TREM2, IL-3Rα, CD22, C5aR1, CX3CR1, P2X7R, CD33, Nrf2, PPAR-γ, CSF1R, and NLRP3, each of which has been discussed in detail. The goal of this review is to put forth the notion that microglia could be targeted by either small molecules or biologics to make the brain microenvironment more amenable to stem cell implantation and propose a novel treatment strategy for future stem cell interventions in AD.
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Affiliation(s)
- Zhiwei Shen
- Department of Neurosurgery, Key laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xinyi Yang
- College of Clinical Medical, Guizhou Medical University, Guiyang, China
| | - Yulong Lan
- Department of Neurosurgery, Key laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Gao Chen
- Department of Neurosurgery, Key laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Joshi R, Missong H, Mishra J, Kaur S, Saini S, Kandimalla R, Reddy PH, Babu A, Bhatti GK, Bhatti JS. Nanotheranostics revolutionizing neurodegenerative diseases: From precision diagnosis to targeted therapies. J Drug Deliv Sci Technol 2023; 89:105067. [DOI: 10.1016/j.jddst.2023.105067] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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12
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Ashraf SS, Hosseinpour Sarmadi V, Larijani G, Naderi Garahgheshlagh S, Ramezani S, Moghadamifar S, Mohebi SL, Brouki Milan P, Haramshahi SMA, Ahmadirad N, Amini N. Regenerative medicine improve neurodegenerative diseases. Cell Tissue Bank 2023; 24:639-650. [PMID: 36527565 DOI: 10.1007/s10561-022-10062-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 12/04/2022] [Indexed: 12/23/2022]
Abstract
Regenerative medicine is a subdivision of medicine that improves methods to regrow, repair or replace unhealthy cells and tissues to return to normal function. Cell therapy, gene therapy, nanomedicine as choices used to cure neurodegenerative disease. Recently, studies related to the treatment of neurodegenerative disorders have been focused on stem cell therapy and Nano-drugs beyond other than regenerative medicine. Hence, by data from experimental models and clinical trials, we review the impact of stem cell therapy, gene therapy, and nanomedicine on the treatment of Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). Indeed, improved knowledge and continued research on gene therapy and nanomedicine in treating Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis lead to advancements in effective and practical treatments for neurodegenerative diseases.
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Affiliation(s)
- Seyedeh Sara Ashraf
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Institutes of Regenerative Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Vahid Hosseinpour Sarmadi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Institutes of Regenerative Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ghazaleh Larijani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Soheila Naderi Garahgheshlagh
- Burn Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Plastic and Reconstructive surgery, Hazrat Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sara Ramezani
- Neuroscience Research Center, Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Guilan, Iran
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Soraya Moghadamifar
- Department of Textile Engineering, Amirkabir University of Technology, Tehran, Iran
| | - Seyedeh Lena Mohebi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Institutes of Regenerative Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Peiman Brouki Milan
- Institutes of Regenerative Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohammad Amin Haramshahi
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Plastic and Reconstructive surgery, Hazrat Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nooshin Ahmadirad
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Naser Amini
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
- Institutes of Regenerative Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Bhatti JS, Khullar N, Mishra J, Kaur S, Sehrawat A, Sharma E, Bhatti GK, Selman A, Reddy PH. Stem cells in the treatment of Alzheimer's disease – Promises and pitfalls. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166712. [DOI: https:/doi.org/10.1016/j.bbadis.2023.166712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
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14
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Bhatti JS, Khullar N, Mishra J, Kaur S, Sehrawat A, Sharma E, Bhatti GK, Selman A, Reddy PH. Stem cells in the treatment of Alzheimer's disease - Promises and pitfalls. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166712. [PMID: 37030521 DOI: 10.1016/j.bbadis.2023.166712] [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: 02/25/2023] [Accepted: 03/31/2023] [Indexed: 04/10/2023]
Abstract
Alzheimer's disease (AD) is the most widespread form of neurodegenerative disorder that causes memory loss and multiple cognitive issues. The underlying mechanisms of AD include the build-up of amyloid-β and phosphorylated tau, synaptic damage, elevated levels of microglia and astrocytes, abnormal microRNAs, mitochondrial dysfunction, hormonal imbalance, and age-related neuronal loss. However, the etiology of AD is complex and involves a multitude of environmental and genetic factors. Currently, available AD medications only alleviate symptoms and do not provide a permanent cure. Therefore, there is a need for therapies that can prevent or reverse cognitive decline, brain tissue loss, and neural instability. Stem cell therapy is a promising treatment for AD because stem cells possess the unique ability to differentiate into any type of cell and maintain their self-renewal. This article provides an overview of the pathophysiology of AD and existing pharmacological treatments. This review article focuses on the role of various types of stem cells in neuroregeneration, the potential challenges, and the future of stem cell-based therapies for AD, including nano delivery and gaps in stem cell technology.
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Affiliation(s)
- Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Naina Khullar
- Department of Zoology, Mata Gujri College, Fatehgarh Sahib, Punjab, India
| | - Jayapriya Mishra
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Satinder Kaur
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Abhishek Sehrawat
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Eva Sharma
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India
| | - Ashley Selman
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA.
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15
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Babaei H, Kheirollah A, Ranjbaran M, Cheraghzadeh M, Sarkaki A, Adelipour M. Preconditioning adipose-derived mesenchymal stem cells with dimethyl fumarate promotes their therapeutic efficacy in the brain tissues of rats with Alzheimer's disease. Biochem Biophys Res Commun 2023; 672:120-127. [PMID: 37348174 DOI: 10.1016/j.bbrc.2023.06.045] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 06/14/2023] [Indexed: 06/24/2023]
Abstract
AIM Transplantation of mesenchymal stem cell (MSC) has been suggested to be a promising method for treating neurodegenerative conditions, including Alzheimer's disease (AD). However, the poor survival rate of transplanted MSCs has limited their therapeutic application. This study aimed to evaluate whether preconditioning MSCs with dimethyl fumarate (DMF), a Nrf2 inducer, could enhance MSC therapeutic efficacy in an amyloid-β (Aβ1-42)-induced AD rat model. METHODS The survival and antioxidant capacity of MSCs treated with DMF were assessed in vitro. Aβ1-42 intrahippocampal injection was used to create a rat model of AD. Following the transplantation of MSCs preconditioned with DMF and using the Morris blue maze test, spatial learning and memory were assessed. Using RT-qPCR, we evaluated the gene expression related to apoptosis and neurotrophins in the hippocampus region. RESULTS Treatment with DMF enhanced cell survival and Nrf2 protein expression in MSCs in vitro. Preconditioning with DMF also enhanced the efficacy of transplanted MSCs in rescuing learning and spatial memory deficits in Aβ-AD rats. Besides, DMF preconditioning enhanced the neuroprotective effect of transplanted MSCs in the hippocampus of rats treated with Aβ1-42 by decreasing the expression of apoptotic markers (Bax, caspase 3, and cytochrome c), and elevating the expression of the anti-apoptotic marker Bcl2 and neurotrophins, including BDNF and NGF. CONCLUSION Preconditioning MSCs with DMF boosted the therapeutic efficacy of these cells; therefore, it could serve as a targeted strategy for increasing the therapeutic efficacy of MSCs in treating neurodegenerative disorders, including AD.
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Affiliation(s)
- Hossein Babaei
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Alireza Kheirollah
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mina Ranjbaran
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Cheraghzadeh
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Alireza Sarkaki
- Medical Plant Research Center, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran; Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Maryam Adelipour
- Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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16
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Biglari N, Mehdizadeh A, Vafaei Mastanabad M, Gharaeikhezri MH, Gol Mohammad Pour Afrakoti L, Pourbala H, Yousefi M, Soltani-Zangbar MS. Application of mesenchymal stem cells (MSCs) in neurodegenerative disorders: History, findings, and prospective challenges. Pathol Res Pract 2023; 247:154541. [PMID: 37245265 DOI: 10.1016/j.prp.2023.154541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/30/2023]
Abstract
Over the past few decades, the application of mesenchymal stem cells has captured the attention of researchers and practitioners worldwide. These cells can be obtained from practically every tissue in the body and are used to treat a broad variety of conditions, most notably neurological diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Studies are still being conducted, and the results of these studies have led to the identification of several different molecular pathways involved in the neuroglial speciation process. These molecular systems are closely regulated and interconnected due to the coordinated efforts of many components that make up the machinery responsible for cell signaling. Within the scope of this study, we compared and contrasted the numerous mesenchymal cell sources and their cellular features. These many sources of mesenchymal cells included adipocyte cells, fetal umbilical cord tissue, and bone marrow. In addition, we investigated whether these cells can potentially treat and modify neurodegenerative illnesses.
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Affiliation(s)
- Negin Biglari
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa Vafaei Mastanabad
- Neurosurgery Department, Faculty of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | | | - Hooman Pourbala
- Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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17
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Marsool MDM, Prajjwal P, Reddy YB, Marsool ADM, Lam JR, Nandwana V. Newer modalities in the management of Alzheimer's dementia along with the role of aducanumab and lecanemab in the treatment of its refractory cases. Dis Mon 2023; 69:101547. [PMID: 36931947 DOI: 10.1016/j.disamonth.2023.101547] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
Abstract
Alzheimer's disease (AD) is a common neurological condition characterized by a gradual and progressive decline in memory, language, emotion, and cognition. It mainly affects elderly people. Due to the effects of AD, pharmaceutical medications and anticholinesterases have been vigorously promoted and approved by the FDA as a form of AD therapy. However, it was progressively found that these drugs did not address the underlying causes of AD pathogenesis; rather, they focused on the symptoms in order to enhance patients' cognitive outcomes. Consequently, a hunt for superior disease-modifying options is launched. Designing new therapeutic agents requires a thorough understanding of the neuroprotective processes and varied functions carried out by certain genes, and antibodies. In this comprehensive review article, we give an overview of the history of Alzheimer's disease, the significance of the blood-brain barrier in determining the scope of treatment options, as well as the advantages and disadvantages of the current therapeutic treatment options for stem cell therapy, immunotherapy, regenerative therapy, and improved Alzheimer's disease care and diagnosis. We have also included a discussion on the potential role of aducanumab and Lecanemab as a cutting-edge therapy in refractory Alzheimer's disease patients. Lecanemab has been recently approved by the FDA for the treatment of Alzheimer's disease.
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Affiliation(s)
| | | | | | | | - Justin Riley Lam
- Internal Medicine, Cebu Institute of Medicine, Cebu, Philippines
| | - Varsha Nandwana
- Neurology, Virginia Tech Carilion School of Medicine, Virginia, USA
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Li X, Zhu Y, Wang Y, Xia X, Zheng JC. Neural stem/progenitor cell-derived extracellular vesicles: A novel therapy for neurological diseases and beyond. MedComm (Beijing) 2023; 4:e214. [PMID: 36776763 PMCID: PMC9905070 DOI: 10.1002/mco2.214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 02/10/2023] Open
Abstract
As bilayer lipid membrane vesicles secreted by neural stem/progenitor cells (NSCs), NSC-derived extracellular vesicles (NSC-EVs) have attracted growing attention for their promising potential to serve as novel therapeutic agents in treatment of neurological diseases due to their unique physicochemical characteristics and biological functions. NSC-EVs exhibit advantages such as stable physical and chemical properties, low immunogenicity, and high penetration capacity to cross blood-brain barrier to avoid predicaments of the clinical applications of NSCs that include autoimmune responses, ethical/religious concerns, and the problematic logistics of acquiring fetal tissues. More importantly, NSC-EVs inherit excellent neuroprotective and neuroregenerative potential and immunomodulatory capabilities from parent cells, and display outstanding therapeutic effects on mitigating behavioral alterations and pathological phenotypes of patients or animals with neurological diseases. In this review, we first comprehensively summarize the progress in functional research and application of NSC-EVs in different neurological diseases, including neurodegenerative diseases, acute neurological diseases, dementia/cognitive dysfunction, and peripheral diseases. Next, we provide our thoughts on current limitations/concerns as well as tremendous potential of NSC-EVs in clinical applications. Last, we discuss future directions of further investigations on NSC-EVs and their probable applications in both basic and clinical research.
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Affiliation(s)
- Xiangyu Li
- Center for Translational Neurodegeneration and Regenerative TherapyTongji Hospital, Tongji University School of MedicineShanghaiChina
| | - Yingbo Zhu
- Center for Translational Neurodegeneration and Regenerative TherapyTongji Hospital, Tongji University School of MedicineShanghaiChina
| | - Yi Wang
- Center for Translational Neurodegeneration and Regenerative TherapyYangzhi Rehabilitation Hospital, Tongji UniversityShanghaiChina
| | - Xiaohuan Xia
- Center for Translational Neurodegeneration and Regenerative TherapyTongji Hospital, Tongji University School of MedicineShanghaiChina
- Shanghai Frontiers Science Center of Nanocatalytic MedicineTongji University School of MedicineShanghaiChina
- Translational Research Institute of Brain and Brain‐Like IntelligenceShanghai Fourth People's Hospital, Tongji University School of MedicineShanghaiChina
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Tongji UniversityMinistry of EducationShanghaiChina
| | - Jialin C. Zheng
- Center for Translational Neurodegeneration and Regenerative TherapyTongji Hospital, Tongji University School of MedicineShanghaiChina
- Shanghai Frontiers Science Center of Nanocatalytic MedicineTongji University School of MedicineShanghaiChina
- Translational Research Institute of Brain and Brain‐Like IntelligenceShanghai Fourth People's Hospital, Tongji University School of MedicineShanghaiChina
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Tongji UniversityMinistry of EducationShanghaiChina
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Duan Y, Lyu L, Zhan S. Stem Cell Therapy for Alzheimer's Disease: A Scoping Review for 2017-2022. Biomedicines 2023; 11:120. [PMID: 36672626 PMCID: PMC9855936 DOI: 10.3390/biomedicines11010120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/28/2022] [Accepted: 12/28/2022] [Indexed: 01/05/2023] Open
Abstract
Alzheimer's disease (AD) has been a major causal factor for mortality among elders around the world. The treatments for AD, however, are still in the stage of development. Stem cell therapy, compared to drug therapies and many other therapeutic options, has many advantages and is very promising in the future. There are four major types of stem cells used in AD therapy: neural stem cells, mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells. All of them have applications in the treatments, either at the (1) cellular level, in an (2) animal model, or at the (3) clinical level. In general, many more types of stem cells were studied on the cellular level and animal model, than the clinical level. We suggest for future studies to increase research on various types of stem cells and include cross-disciplinary research with other diseases. In the future, there could also be improvements in the timeliness of research and individualization for stem cell therapies for AD.
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Affiliation(s)
- Yunxiao Duan
- Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA
| | - Linshuoshuo Lyu
- Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA
| | - Siyan Zhan
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
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20
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Toledano-Díaz A, Álvarez MI, Toledano A. The relationships between neuroglial and neuronal changes in Alzheimer's disease, and the related controversies II: gliotherapies and multimodal therapy. J Cent Nerv Syst Dis 2022; 14:11795735221123896. [PMID: 36407561 PMCID: PMC9666878 DOI: 10.1177/11795735221123896] [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: 08/18/2021] [Accepted: 08/05/2022] [Indexed: 08/30/2023] Open
Abstract
Since the original description of Alzheimer´s disease (AD), research into this condition has mainly focused on assessing the alterations to neurons associated with dementia, and those to the circuits in which they are involved. In most of the studies on human brains and in many models of AD, the glial cells accompanying these neurons undergo concomitant alterations that aggravate the course of neurodegeneration. As a result, these changes to neuroglial cells are now included in all the "pathogenic cascades" described in AD. Accordingly, astrogliosis and microgliosis, the main components of neuroinflammation, have been integrated into all the pathogenic theories of this disease, as discussed in this part of the two-part monograph that follows an accompanying article on gliopathogenesis and glioprotection. This initial reflection verified the implication of alterations to the neuroglia in AD, suggesting that these cells may also represent therapeutic targets to prevent neurodegeneration. In this second part of the monograph, we will analyze the possibilities of acting on glial cells to prevent or treat the neurodegeneration that is the hallmark of AD and other pathologies. Evidence of the potential of different pharmacological, non-pharmacological, cell and gene therapies (widely treated) to prevent or treat this disease is now forthcoming, in most cases as adjuncts to other therapies. A comprehensive AD multimodal therapy is proposed in which neuronal and neuroglial pharmacological treatments are jointly considered, as well as the use of new cell and gene therapies and non-pharmacological therapies that tend to slow down the progress of dementia.
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21
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In vitro effects of H2O2 on neural stem cell differentiation. In Vitro Cell Dev Biol Anim 2022; 58:810-816. [DOI: 10.1007/s11626-022-00723-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 09/15/2022] [Indexed: 11/26/2022]
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22
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CX3CL1 Derived from Bone Marrow Mesenchymal Stem Cells Inhibits Aβ1-42-Induced SH-SY5Y Cell Pathological Damage through TXNIP/NLRP3 Signaling Pathway. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:1949344. [PMID: 36118839 PMCID: PMC9477634 DOI: 10.1155/2022/1949344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/14/2022] [Accepted: 07/25/2022] [Indexed: 11/25/2022]
Abstract
Alzheimer's disease (AD) is the most commonly seen neurodegenerative brain disorder. The paracrine effects of mesenchymal stem cells (MSCs) signify to trigger immunomodulation and neural regeneration. However, the role and mechanism of bone marrow MSC- (BMSC-) derived CX3CL1 in AD remains elusive. In this study, Aβ1-42-intervened SH-SY5Y cells were used for AD cell model construction. pcDNA-ligated CX3CL1 overexpression plasmids were transfected into BMSCs. The levels of soluble and membrane-bound CX3CL1 were detected by ELISA and Western blotting (WB), respectively. The growth, apoptosis, and pathology of AD model cells were evaluated by CCK-8, flow cytometry, immunofluorescence, morphology observation, biochemical examination, and WB. It was found that Aβ1-42 significantly reduced CX3CL1 expression either in soluble or membrane-bound form, cell viability, relative protein expression of synaptic markers, SOD, CAT, and GSH-Px contents, as well as Trx protein expression; in addition, it enhanced the apoptosis rate, the relative expression of cleaved caspase-3, Aβ, tau, p-Tau, Iba1, MDA, TXNIP, and NLRP3 in SH-SY5Y cells; however, the above effects were prominently reversed by the coculture of BMSCs. Moreover, overexpression of CX3CL1 in BMSCs observably strengthened the corresponding tendency caused by BMSCs. In conclusion, through the TXNIP/NLRP3 pathway, CX3CL1 derived from BMSCs inhibited pathological damage in Aβ1-42-induced SH-SY5Y.
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23
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Ahmad F, Sachdeva P. A consolidated review on stem cell therapy for treatment and management of Alzheimer's disease. Aging Med (Milton) 2022; 5:182-190. [PMID: 36247342 PMCID: PMC9549310 DOI: 10.1002/agm2.12216] [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: 06/05/2022] [Revised: 07/08/2022] [Accepted: 07/11/2022] [Indexed: 11/06/2022] Open
Abstract
Alzheimer's disease (AD) is one of the most common forms of dementia and affects around 50 million people around the globe. AD is diagnosed mainly through imaging techniques and to date only five drugs are approved for management of AD but no promising treatment is available for AD. So in this review, we are focusing on stem cell therapy for AD. This review will cover all stem cells like mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, and neural stem cells. Clinical trials of AD have also been discussed. Finally, limitations of stem cells are discussed with ongoing clinical trials, and in the future stem cell therapy can be used for treatment of AD.
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Affiliation(s)
- Faizan Ahmad
- Department of Medical Elementology and ToxicologyJamia Hamdard UniversityDelhiIndia
| | - Punya Sachdeva
- Amity Institute of Neuropsychology and NeurosciencesAmity UniversityNoidaUttar PradeshIndia
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24
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Pharmacotherapy of Alzheimer's disease: an overview of systematic reviews. Eur J Clin Pharmacol 2022; 78:1567-1587. [PMID: 35881170 DOI: 10.1007/s00228-022-03363-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 07/02/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia. In this umbrella systematic review (SR), we summarized the efficacy of different pharmacological interventions in improving cognitive function in patients with AD. METHODS A systematic search was performed through the PubMed, Scopus, Embase, and Cochrane databases for SRs of studies assessing the efficacy of pharmacological interventions versus placebo in improving cognitive function in AD or mild cognitive impairment due to AD. The risk of bias (RoB) was assessed using the Risk of Bias in SRs (ROBIS) tool. RESULTS Out of 1748 articles found through the database survey, 33 SR articles were included. These studies assessed effects of immunotherapy, cholinesterase inhibitors (ChEIs), memantine, statins, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs), antidiabetic agents, Cerebrolysin, RAS-targeting antihypertensive drugs (ARBs and ACEIs), psychostimulants, glycogen synthase kinase 3 (GSK-3) inhibitors, melatonin, and herbal medications on cognitive function in AD patients. There was no notable overall RoB in 18 studies (54.5%), the RoB in 14 studies (42.4%) was high, and in one study (3.0%) it was unclear. CONCLUSIONS The use of ChEIs, including rivastigmine, galantamine, and donepezil, as well as memantine has demonstrated a positive impact on improving cognitive outcomes of AD patients, but no considerable effects were found for immunotherapies. Melatonin, statins, antihypertensive drugs, antidiabetic agents, Cerebrolysin, psychostimulants, and some herbal drugs such as Danggui-Shaoyao-San and Ginkgo biloba seem to be effective in improving cognitive function of AD patients, but the evidence in this regard is limited.
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25
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Li DD, Zheng CQ, Zhang F, Shi JS. Potential neuroprotection by Dendrobium nobile Lindl alkaloid in Alzheimer's disease models. Neural Regen Res 2022; 17:972-977. [PMID: 34558510 PMCID: PMC8552836 DOI: 10.4103/1673-5374.324824] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/20/2021] [Accepted: 02/20/2021] [Indexed: 01/05/2023] Open
Abstract
At present, treatments for Alzheimer's disease can temporarily relieve symptoms but cannot prevent the decline of cognitive ability and other neurodegenerative changes. Dendrobium nobile Lindl alkaloid is the main active component of Dendrobium nobile Lindl. Dendrobium nobile Lindl alkaloid has been shown to resist aging, prolong life span, and exhibit immunomodulatory effects in animals. This review summarizes the mechanisms behind the neuroprotective effects reported in Alzheimer's disease animal models. The neuroprotective effects of Dendrobium nobile Lindl alkaloid have not been studied in patients. The mechanisms by which Dendrobium nobile Lindl alkaloid has been reported to improve cognitive dysfunction in Alzheimer's disease animal models may be associated with extracellular amyloid plaque production, regulation of tau protein hyperphosphorylation, inhibition of neuroinflammation and neuronal apoptosis, activation of autophagy, and enhanced synaptic connections.
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Affiliation(s)
- Dai-Di Li
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Lab of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou Province, China
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chang-Qing Zheng
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Lab of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Feng Zhang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Lab of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Jing-Shan Shi
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Lab of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou Province, China
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26
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Zhou C, Ni W, Zhu T, Dong S, Sun P, Hua F. Cellular Reprogramming and Its Potential Application in Alzheimer's Disease. Front Neurosci 2022; 16:884667. [PMID: 35464309 PMCID: PMC9023048 DOI: 10.3389/fnins.2022.884667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 03/15/2022] [Indexed: 11/13/2022] Open
Abstract
Alzheimer's disease (AD) has become the most common age-related dementia in the world and is currently incurable. Although many efforts have been made, the underlying mechanisms of AD remain unclear. Extracellular amyloid-beta deposition, intracellular tau hyperphosphorylation, neuronal death, glial cell activation, white matter damage, blood-brain barrier disruption, and other mechanisms all take part in this complicated disease, making it difficult to find an effective therapy. In the study of therapeutic methods, how to restore functional neurons and integrate myelin becomes the main point. In recent years, with the improvement and maturity of induced pluripotent stem cell technology and direct cell reprogramming technology, it has become possible to induce non-neuronal cells, such as fibroblasts or glial cells, directly into neuronal cells in vitro and in vivo. Remarkably, the induced neurons are functional and capable of entering the local neural net. These encouraging results provide a potential new approach for AD therapy. In this review, we summarized the characteristics of AD, the reprogramming technique, and the current research on the application of cellular reprogramming in AD. The existing problems regarding cellular reprogramming and its therapeutic potential for AD were also reviewed.
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Affiliation(s)
- Chao Zhou
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Wanyan Ni
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Taiyang Zhu
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Shuyu Dong
- Department of Neurology, Xuzhou Central Hospital, Xuzhou, China
| | - Ping Sun
- Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Fang Hua
- Institute of Neurological Diseases, Xuzhou Medical University, Xuzhou, China
- Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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Rezk S, Lashen S, El-Adl M, Elshopakey GE, Elghareeb MM, Hendam BM, Caceci T, Cenciarelli C, Marei HE. Effects of Rosemary Oil (Rosmarinus officinalis) supplementation on the fate of the transplanted human olfactory bulb neural stem cells against ibotenic acid-induced neurotoxicity (Alzheimer model) in rat. Metab Brain Dis 2022; 37:973-988. [PMID: 35075502 DOI: 10.1007/s11011-021-00890-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/05/2021] [Indexed: 12/16/2022]
Abstract
Rosemary oil (ROO) is known to have multiple pharmacological effects: it is an antioxidant, anti-inflammatory, and cytoprotective. In the present study, we examined the effects of ROO on Human olfactory bulb neuronal stem cells (hOBNSCs) after their transplantation into rats, with the ibotenic (IBO) acid-induced cognitive deficit model. After 7 weeks, cognitive functions were assessed using the Morris water maze (MWM). After two months blood and hippocampus samples were collected for biochemical, gene expression, and histomorphometric analyses. Learning ability and memory function were significantly enhanced (P < 0.05) after hOBNSCs transplantation and were nearly returned to normal in the treated group. The IBO acid injection was associated with a significant decline (P < 0.05) of total leukocyte count (TLC) and a significant increase (P < 0.05) in total and toxic neutrophils. As well, the level of IL-1β, TNF-α CRP in serum and levels of MDA and NO in hippocampus tissue were significantly elevated (P < 0.05), while antioxidant markers (CAT, GSH, and SOD) were reduced (P < 0.05) in treated tissue compared to controls. The administration of ROO before or with cell transplantation attenuated all these parameters. In particular, the level of NO nearly returned to normal when rosemary was administrated before cell transplantation. Gene expression analysis revealed the potential protective effect of ROO and hOBNSCs via down-expression of R-βAmyl and R- CAS 3 and R-GFAP genes. The improvement in the histological organization of the hippocampus was detected after the hOBNSCs transplantation especially in h/ROO/hOBNSCs group.
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Affiliation(s)
- Shaymaa Rezk
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Samah Lashen
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Mohamed El-Adl
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Gehad E Elshopakey
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt.
| | - Mona M Elghareeb
- Department of Physiology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Basma M Hendam
- Department of Husbandry & Development of Animal Wealth, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Thomas Caceci
- Biomedical Sciences and Pathobiology, Virginia Maryland College of Veterinary Medicine , Blacksburg, VA, USA
| | - Carlo Cenciarelli
- Departament of Biomedical Sciences, Institute of Translational Pharmacology-CNR, Rome, Italy
| | - Hany E Marei
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
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28
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Reinitz F, Chen EY, Nicolis di Robilant B, Chuluun B, Antony J, Jones RC, Gubbi N, Lee K, Ho WHD, Kolluru SS, Qian D, Adorno M, Piltti K, Anderson A, Monje M, Heller HC, Quake SR, Clarke MF. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model. eLife 2022; 11:66037. [PMID: 35311644 PMCID: PMC9122497 DOI: 10.7554/elife.66037] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/17/2022] [Indexed: 11/23/2022] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.
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Affiliation(s)
- Felicia Reinitz
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Elizabeth Y Chen
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Benedetta Nicolis di Robilant
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | | | - Jane Antony
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Robert C Jones
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Neha Gubbi
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Karen Lee
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - William Hai Dang Ho
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Sai Saroja Kolluru
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Dalong Qian
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Maddalena Adorno
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Katja Piltti
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
| | - Aileen Anderson
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
| | - Michelle Monje
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - H Craig Heller
- Department of Biology, Stanford University, Stanford, United States
| | - Stephen R Quake
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Michael F Clarke
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
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29
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Lim JY, Lee JE, Park SA, Park SI, Yon JM, Park JA, Jeun SS, Kim SJ, Lee HJ, Kim SW, Yang SH. Protective Effect of Human-Neural-Crest-Derived Nasal Turbinate Stem Cells against Amyloid-β Neurotoxicity through Inhibition of Osteopontin in a Human Cerebral Organoid Model of Alzheimer’s Disease. Cells 2022; 11:cells11061029. [PMID: 35326480 PMCID: PMC8947560 DOI: 10.3390/cells11061029] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/14/2022] [Accepted: 03/16/2022] [Indexed: 11/16/2022] Open
Abstract
The aim of this study was to validate the use of human brain organoids (hBOs) to investigate the therapeutic potential and mechanism of human-neural-crest-derived nasal turbinate stem cells (hNTSCs) in models of Alzheimer’s disease (AD). We generated hBOs from human induced pluripotent stem cells, investigated their characteristics according to neuronal markers and electrophysiological features, and then evaluated the protective effect of hNTSCs against amyloid-β peptide (Aβ1–42) neurotoxic activity in vitro in hBOs and in vivo in a mouse model of AD. Treatment of hBOs with Aβ1–42 induced neuronal cell death concomitant with decreased expression of neuronal markers, which was suppressed by hNTSCs cocultured under Aβ1–42 exposure. Cytokine array showed a significantly decreased level of osteopontin (OPN) in hBOs with hNTSC coculture compared with hBOs only in the presence of Aβ1–42. Silencing OPN via siRNA suppressed Aβ-induced neuronal cell death in cell culture. Notably, compared with PBS, hNTSC transplantation significantly enhanced performance on the Morris water maze, with reduced levels of OPN after transplantation in a mouse model of AD. These findings reveal that hBO models are useful to evaluate the therapeutic effect and mechanism of stem cells for application in treating AD.
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Affiliation(s)
- Jung Yeon Lim
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jung Eun Lee
- Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Kyonggi-do, Korea
| | - Soon A Park
- Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Sang In Park
- Institute of Catholic Integrative Medicine (ICIM), Incheon St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Korea
| | - Jung-Min Yon
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Jeong-Ah Park
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Sin-Soo Jeun
- Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Seung Joon Kim
- Division of Pulmonology, Critical Care and Allergy, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Hong Jun Lee
- College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju 28644, Korea
| | - Sung Won Kim
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Seung Ho Yang
- Department of Neurosurgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon 16247, Kyonggi-do, Korea
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30
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Karvelas N, Bennett S, Politis G, Kouris NI, Kole C. Advances in stem cell therapy in Alzheimer's disease: a comprehensive clinical trial review. Stem Cell Investig 2022; 9:2. [PMID: 35280344 PMCID: PMC8898169 DOI: 10.21037/sci-2021-063] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/27/2022] [Indexed: 07/30/2023]
Abstract
Alzheimer's disease (AD) is the most common type of dementia responsible for more than 121,499 deaths from AD in 2019 making AD the sixth-leading cause in the United States. AD is a progressive neurodegenerative disorder characterized by decline of memory, behavioral impairments that affects a person's ability to function independently ultimately leading to death. The current pressing need for a treatment for (AD) and advances in the field of cell therapy, has rendered stem cell therapeutics a promising field of research. Despite advancements in stem cell technology, confirmed by encouraging pre-clinical utilization of stem cells in AD animal models, the number of clinical trials evaluating the efficacy of stem cell therapy is limited, with the results of many ongoing clinical trials on cell therapy for AD still pending. Mesenchymal stem cells (MSCs) have been the main focus in these studies, reporting encouraging results concerning safety profile, however their efficacy remains unproven. In the current article we review the latest advances regarding different sources of stem cell therapy and present a comprehensive list of every available clinical trial in national and international registries. Finally, we discuss drawbacks arising from AD pathology and technical limitations that hinder the transition of stem cell technology from bench to bedside. Our findings emphasize the need to increase clinical trials towards uncovering the mode of action and the underlying therapeutic mechanisms of transplanted cells as well as the molecular mechanisms controlling regeneration and neuronal microenvironment.
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Affiliation(s)
- Nikolaos Karvelas
- Faculty of Medicine, National and Kapodistrian University of Athens, Athina, Greece
| | | | - Georgios Politis
- Faculty of Medicine, National and Kapodistrian University of Athens, Athina, Greece
| | | | - Christo Kole
- Faculty of Medicine, National and Kapodistrian University of Athens, Athina, Greece
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31
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Liu B, Li M, Zhang L, Chen Z, Lu P. Motor neuron replacement therapy for amyotrophic lateral sclerosis. Neural Regen Res 2022; 17:1633-1639. [PMID: 35017408 PMCID: PMC8820706 DOI: 10.4103/1673-5374.332123] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig's disease in the United States, Charcot's disease in France, and motor neuron disease in the UK. The loss of motor neurons causes muscle wasting, paralysis, and eventually death, which is commonly related to respiratory failure, within 3-5 years after onset of the disease. Although there are a limited number of drugs approved for amyotrophic lateral sclerosis, they have had little success at treating the associated symptoms, and they cannot reverse the course of motor neuron degeneration. Thus, there is still a lack of effective treatment for this debilitating neurodegenerative disorder. Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers, particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons. Stem cell therapies may also be able to re-establish the motor control of voluntary muscles. Here, we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis. We focus on MN progenitor cells derived from fetal central nervous system tissue, embryonic stem cells, and induced pluripotent stem cells. In our recent studies, we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well, differentiate into motor neurons, and extend axons into the host white matter, not only in the rostrocaudal direction, but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord. Furthermore, the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis, particularly as a variety of stem cell derivatives, including induced pluripotent stem cells, are being considered for clinical trials for various diseases.
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Affiliation(s)
- Bochao Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education; Center of Neural Injury and Repair; Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Mo Li
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education; Center of Neural Injury and Repair; Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Lingyan Zhang
- iXCells Biotechnologies USA, Inc., San Diego, CA, USA; Amogene Biotech, Xiamen, Fujian Province, China
| | - Zhiguo Chen
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education; Center of Neural Injury and Repair; Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Paul Lu
- Veterans Administration San Diego Healthcare System, San Diego; Department of Neurosciences, University of California - San Diego, La Jolla, CA, USA
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32
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Zhao X, Li D, Zhang L, Niu Y, Wang W, Niu B. Mesenchymal stem cell therapies for Alzheimer's disease: preclinical studies. Metab Brain Dis 2021; 36:1687-1695. [PMID: 34213730 DOI: 10.1007/s11011-021-00777-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/06/2021] [Indexed: 12/17/2022]
Abstract
Alzheimer's disease (AD) is a chronic, progressive, and fatal neurodegenerative disorder that is characterized by memory failure, cognitive impairment, as well as behavioral and psychological manifestations. Drugs can only moderately manage, but not alleviate, clinical symptoms. Results, based on animal models, have demonstrated that cell therapy is a promising strategy for treating neurodegenerative disorders. The homing effect of mesenchymal stem cells (MSCs) replaces damaged cells, while some scholars believe that the paracrine effects play a crucial role in treating diseases. In fact, these cells have rich sources, exhibit high proliferation rates, low tumorigenicity, and immunogenicity, and have no ethical concerns. Consequently, MSCs have been used across various disease aspects, such as regulating immunity, nourishing nerves, and promoting regeneration. Deterioration of public health status have exposed both Alzheimer's patients and researchers to various difficulties during epidemics. In this review, we discuss the advances and challenges in the application of mesenchymal stem cell therapy for treatment of Alzheimer's disease.
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Affiliation(s)
- Xiaorong Zhao
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Dandan Li
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Li Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Yuhu Niu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Wenzhuo Wang
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Bo Niu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
- Department of Biotechnology, Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
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Mesenchymal Stem Cell Therapy for Alzheimer's Disease. Stem Cells Int 2021; 2021:7834421. [PMID: 34512767 PMCID: PMC8426054 DOI: 10.1155/2021/7834421] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/09/2021] [Indexed: 12/17/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease responsible for 60-70% of the 50 million cases of dementia worldwide. It is characterized by neuronal cell death, shrinkage of brain tissue, and progressive cognitive, motor, and behavioral impairment, which often leads to death. Although current treatment has helped improve the patient's quality of life, it has not been able to alter the underlying disease pathology of AD. Studies have shown that mesenchymal stem cells (MSCs)—a group of multipotent stem cells—have the ability to stimulate neuroregeneration and inhibit disease progression. More recently, extracellular vesicles (EVs) from cytokine-preconditioned MSCs have also shown to induce immunomodulatory and neuroprotective effects in AD models. This review will aim to compile pertinent preclinical AD research on transgenic mice as well as clinical trials on MSC-based therapy from diverse sources.
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Lim JY, In Park S, Park SA, Jeon JH, Jung HY, Yon JM, Jeun SS, Lim HK, Kim SW. Potential application of human neural crest-derived nasal turbinate stem cells for the treatment of neuropathology and impaired cognition in models of Alzheimer's disease. Stem Cell Res Ther 2021; 12:402. [PMID: 34256823 PMCID: PMC8278635 DOI: 10.1186/s13287-021-02489-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 07/02/2021] [Indexed: 12/21/2022] Open
Abstract
Background Stem cell transplantation is a fascinating therapeutic approach for the treatment of many neurodegenerative disorders; however, clinical trials using stem cells have not been as effective as expected based on preclinical studies. The aim of this study is to validate the hypothesis that human neural crest-derived nasal turbinate stem cells (hNTSCs) are a clinically promising therapeutic source of adult stem cells for the treatment of Alzheimer’s disease (AD). Methods hNTSCs were evaluated in comparison with human bone marrow-derived mesenchymal stem cells (hBM-MSCs) according to the effect of transplantation on AD pathology, including PET/CT neuroimaging, immune status indicated by microglial numbers and autophagic capacity, neuronal survival, and cognition, in a 5 × FAD transgenic mouse model of AD. Results We demonstrated that hNTSCs showed a high proliferative capacity and great neurogenic properties in vitro. Compared with hBM-MSC transplantation, hNTSC transplantation markedly reduced Aβ42 levels and plaque formation in the brains of the 5 × FAD transgenic AD mice on neuroimaging, concomitant with increased survival of hippocampal and cortex neurons. Moreover, hNTSCs strongly modulated immune status by reducing the number of microglia and the expression of the inflammatory cytokine IL-6 and upregulating autophagic capacity at 7 weeks after transplantation in AD models. Notably, compared with transplantation of hBM-MSCs, transplantation of hNTSCs significantly enhanced performance on the Morris water maze, with an increased level of TIMP2, which is necessary for spatial memory in young mice and neurons; this difference could be explained by the high engraftment of hNTSCs after transplantation. Conclusion The reliable evidence provided by these findings reveals a promising therapeutic effect of hNTSCs and indicates a step forward the clinical application of hNTSCs in patients with AD.
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Affiliation(s)
- Jung Yeon Lim
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea.
| | - Sang In Park
- Institute of Catholic Integrative Medicine (ICIM), Incheon St. Mary's Hospital, The Catholic University of Korea, 56 Dongsu-ro, Bupyeong-gu, Incheon, 21431, Republic of Korea
| | - Soon A Park
- Department of Neurosurgery, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Jung Ho Jeon
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Ho Yong Jung
- Institute of Catholic Integrative Medicine (ICIM), Incheon St. Mary's Hospital, The Catholic University of Korea, 56 Dongsu-ro, Bupyeong-gu, Incheon, 21431, Republic of Korea
| | - Jung-Min Yon
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Sin-Soo Jeun
- Department of Neurosurgery, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Hyun Kook Lim
- Department of Psychiatry, Yeouido St. Mary's Hospital, The Catholic University of Korea, 63-ro 10, Yeoungdeungpo-gu, Seoul, 07345, Republic of Korea
| | - Sung Won Kim
- Department of Otolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea.
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35
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He Z, Song J, Li X, Li X, Zhu H, Wu C, Xiao W, Du X, Ni J, Li N, Liu Q. Bis(ethylmaltolato)oxidovanadium (IV) alleviates neuronal apoptosis through regulating peroxisome proliferator-activated receptor γ in a triple transgenic animal model of Alzheimer's disease. J Biol Inorg Chem 2021; 26:551-568. [PMID: 34240269 DOI: 10.1007/s00775-021-01874-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 05/16/2021] [Indexed: 12/27/2022]
Abstract
Endoplasmic reticulum stress (ER stress) plays a critical role in neuronal apoptosis along with the aggravation of Alzheimer's disease (AD). Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that is involved in regulating ER stress in Alzheimer's disease (AD), therefore, this protein could be a promising therapeutic target for AD. Vanadium compounds, such as vanadyl acetylacetonate, sodium metavanadate and bis(maltolato)oxovanadium, are well-known as puissant PPARγ modulators. Thus, we are curious whether bis(ethylmaltolato)oxidovanadium (IV) (BEOV) can ameliorate ER stress and subsequent neuronal apoptosis by regulating PPARγ in AD models. To this end, we determined the effect of BEOV on behavioral performance, ER stress and neuronal apoptosis in the triple transgenic mouse AD model (3×Tg-AD). Our results showed that BEOV improved cognitive abilities and reduced the ER stress- and apoptosis-associated proteins in the brains of 3×Tg-AD mice. In vitro administration of BEOV in primary hippocampal neurons and N2asw cells achieved similar results in repressing ER stress. In addition, cotreatment with GW9662 (an antagonist of PPARγ) effectively blocked these neuroprotective effects of BEOV, which provided strong evidence that PPARγ-dependent signaling plays a key role in protecting against ER stress and neuronal apoptosis in AD. In conclusion, our data demonstrated that BEOV alleviated neuronal apoptosis triggered by ER stress by regulating PPARγ in a 3×Tg-AD model.
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Affiliation(s)
- Zhijun He
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China.,Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| | - Jianxi Song
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Xuexia Li
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China.,Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| | - Xiaoqian Li
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Huazhang Zhu
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Chong Wu
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Wen Xiao
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Xiubo Du
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China
| | - Jiazuan Ni
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China.,Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| | - Nan Li
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China. .,Shenzhen Bay Laboratory, Shenzhen, 518055, China.
| | - Qiong Liu
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, 518055, Guangdong, China. .,Shenzhen-Hong Kong Institute of Brain Science, Shenzhen, 518033, China.
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Liu J, Hou Z, Wu J, Liu K, Li D, Gao T, Liu W, An B, Sun Y, Mo F, Wang L, Wang Y, Hao J, Hu B. Infusion of hESC derived Immunity-and-matrix regulatory cells improves cognitive ability in early-stage AD mice. Cell Prolif 2021; 54:e13085. [PMID: 34232542 PMCID: PMC8349653 DOI: 10.1111/cpr.13085] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/17/2021] [Accepted: 05/22/2021] [Indexed: 12/20/2022] Open
Abstract
Objectives In this study, we administered immunity‐and‐matrix regulatory cells (IMRCs) via tail vein (IV) and intracerebroventricular (ICV) injection to 3‐month‐old 5×FAD transgenic mice to assess the effects of IMRC transplantation on the behaviour and pathology of early‐stage Alzheimer's disease (AD). Materials and methods Clinical‐grade human embryonic stem cell (hESC)‐derived IMRCs were produced under good manufacturing practice (GMP) conditions. Three‐month‐old 5×FAD mice were administered IMRCs via IV and ICV injection. After 3 months, the mice were subjected to behavioural tests and electrophysiological analysis to evaluate their cognitive function, memory ability and synaptic plasticity. The effect of IMRCs on amyloid‐beta (Aβ)‐related pathology was detected by thioflavin‐S staining and Western blot. Quantitative real‐time PCR, ELISA and immunostaining were used to confirm that IMRCs inhibit neuroinflammation. RNA‐seq analysis was performed to measure changes in gene expression and perform a pathway analysis in response to IMRC treatment. Results IMRC administration via tail vein injection significantly ameliorated cognitive deficits in early‐stage AD (5×FAD) mice. However, no significant change was observed in the characteristic pathology of AD in the ICV group. Plaque analysis revealed that IMRCs did not influence either plaque deposition or BACE1 expression. In addition, IMRCs inhibited inflammatory responses and reduced microglial activation in vivo. Conclusions We have shown that peripheral administration of IMRCs can ameliorate AD pathology and associated cognitive deficits.
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Affiliation(s)
- Jing Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Zongren Hou
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Jun Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Kailun Liu
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
| | - Da Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Tingting Gao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Wenjing Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Bin An
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Yun Sun
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Fan Mo
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Liu Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Yukai Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
| | - Baoyang Hu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.,National Stem Cell Resource Center, Chinese Academy of Sciences, Beijing, China
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Pranskunas M, Simoliunas E, Alksne M, Kaupinis A, Juodzbalys G. Periosteum-Derived Mesenchymal Stem Cells Secretome - Cell-Free Strategy for Endogenous Bone Regeneration: Proteomic Analysis in Vitro. EJOURNAL OF ORAL MAXILLOFACIAL RESEARCH 2021; 12:e2. [PMID: 34377379 PMCID: PMC8326881 DOI: 10.5037/jomr.2021.12202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 06/22/2021] [Indexed: 12/29/2022]
Abstract
Objectives Millions of people worldwide are affected by diseases or injuries which lead to bone/tooth loss and defects. While such clinical situations are daily practice in most of the hospitals, the widely used treatment methods still have disadvantages. Therefore, this field of medicine is actively searching new tissue regeneration techniques, one of which could be stem cell secretome. Thus, the purpose of this research study was to perform the detail proteomic analysis of periosteum-derived mesenchymal stem cells secretome in order to evaluate if it is capable to induce osteo-regenerative process. Material and Methods Periosteum-derived mesenchymal stem cells (PMSCs) were extracted from adult male New Zealand White rabbits. Cells were characterised by evaluating their differentiation potential. After characterisation PMSCs secretomes were collected and their proteomic analysis was performed. Results PMSCs were extracted from adult male New Zealand White rabbits. In order to characterise the extracted PMSCs, they were differentiated in the directions which mainly describes MSC multipotency - osteogenic, myogenic and adipogenic. A total of 146 proteins were detected. After characterisation PMSCs secretomes were collected and their proteomic analysis was performed. The resulting protein composition indicates the ability to promote bone regeneration to fully mature bone. Conclusions Bioactive molecules detected in periosteum-derived mesenchymal stem cells secretome initiates the processes required for the formation of a fully functional bone.
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Affiliation(s)
- Mindaugas Pranskunas
- Department of Oral and Maxillofacial Surgery, Faculty of Odontology, Medical Academy, Lithuanian University of Health Sciences, KaunasLithuania.,32:Baltic dental clinic, VilniusLithuania.,These authors contributed equally to this work
| | - Egidijus Simoliunas
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, VilniusLithuania.,These authors contributed equally to this work
| | - Milda Alksne
- Department of Biological Models, Institute of Biochemistry, Life Sciences Center, Vilnius University, VilniusLithuania.,These authors contributed equally to this work
| | - Algirdas Kaupinis
- Proteomics Centre, Institute of Biochemistry, Life Sciences Center, Vilnius University, Saulėtekio av. 7, LT-10257 VilniusLithuania
| | - Gintaras Juodzbalys
- Department of Oral and Maxillofacial Surgery, Faculty of Odontology, Medical Academy, Lithuanian University of Health Sciences, KaunasLithuania.,These authors contributed equally to this work
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38
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Grigorita O, Omer L, Juodzbalys G. Complications and Management of Patients with Inherited Bleeding Disorders During Dental Extractions: a Systematic Literature Review. EJOURNAL OF ORAL MAXILLOFACIAL RESEARCH 2021; 12:e1. [PMID: 34377378 PMCID: PMC8326879 DOI: 10.5037/jomr.2021.12201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/21/2021] [Indexed: 12/26/2022]
Abstract
Objectives The systematic literature review aims to assess patients' dental extraction with inherited bleeding disorders, to understand the type, dosage, and modality of administration of the haemostatic agents for safe intra- and postoperational results. Material and Methods The search was undertaken in MEDLINE (PubMed) databases and Cochrane library for articles published in English from 1 January, 2010 till 31 October, 2020. Before the full-text articles were considered, titles and abstracts were screened. Results A total of 78 articles were screened, from which 3 met the necessary criteria and were used for the review. Minor complications, such as postoperative bleedings from the socket and epistaxis, were observed, but they were resolved with proper medical care. No major fatal complications were reported. Generally, all the articles provided evidence of successful extractions with correct treatment plans made by haematologists and surgeons. Conclusions Available clinical trials demonstrate that local and systemic haemostatic therapies in combination are effective in preventing bleeding during dental extractions in patients with coagulopathies.
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Affiliation(s)
- Olga Grigorita
- Department of Oral and Maxillofacial Surgery, Lithuanian University of Health SciencesLithuania
| | - Loran Omer
- Department of Oral and Maxillofacial Surgery, Lithuanian University of Health SciencesLithuania
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Extracellular vesicles isolated from mesenchymal stromal cells primed with neurotrophic factors and signaling modifiers as potential therapeutics for neurodegenerative diseases. Curr Res Transl Med 2021; 69:103286. [DOI: 10.1016/j.retram.2021.103286] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 02/10/2021] [Accepted: 03/01/2021] [Indexed: 12/17/2022]
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40
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Singh S, Chawla H, Chandra A, Garg S. Magnetic hybrid nanoparticles for drug delivery. MAGNETIC NANOPARTICLE-BASED HYBRID MATERIALS 2021:319-342. [DOI: 10.1016/b978-0-12-823688-8.00034-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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41
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Hunyara JL, Kolodkin AL. Repurposing developmental mechanisms in the adult nervous system. Curr Opin Genet Dev 2020; 65:14-21. [PMID: 32485480 PMCID: PMC10668600 DOI: 10.1016/j.gde.2020.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 04/15/2020] [Indexed: 12/26/2022]
Abstract
Molecules and cellular processes important for nervous system development can be repurposed in adulthood for the regulation of adult neurogenesis, synaptic plasticity, and neural regeneration following injury or degeneration. Efforts to recapitulate neural development in order to ameliorate injury or disease are promising, but these often fall short of functional restoration due in part to our incomplete understanding of how these damaged circuits initially developed. Despite these limitations, such strategies provide hope that harnessing developmental mechanisms can restore nervous system functions following damage or disease.
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Affiliation(s)
- John L Hunyara
- The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
| | - Alex L Kolodkin
- The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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42
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Goudarzi G, Hamidabadi HG, Bojnordi MN, Hedayatpour A, Niapour A, Zahiri M, Absalan F, Darabi S. Role of cerebrospinal fluid in differentiation of human dental pulp stem cells into neuron-like cells. Anat Cell Biol 2020; 53:292-300. [PMID: 32993279 PMCID: PMC7527124 DOI: 10.5115/acb.19.241] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 07/13/2020] [Accepted: 07/30/2020] [Indexed: 02/07/2023] Open
Abstract
Human dental pulp stem cells (hDPSCs) could be differentiated into neuron like-cells under particular microenvironments. It has been reported that a wide range of factors, presented in cerebrospinal fluid (CSF), playing part in neuronal differentiation during embryonic stages, we herein introduce a novel culture media complex to differentiate hDPSCs into neuron-like cells. The hDPSCs were initially isolated and characterized. The CSF was prepared from the Cisterna magna of 19-day-old Wistar rat embryos, embryonic cerebrospinal fluid (E-CSF). The hDPSCs were treated by 5% E-CSF for 2 days, then neurospheres were cultured in DMEM/F12 supplemented with 10-6 μm retinoic acid (RA), glial-derived neurotrophic factor and brain-derived neurotrophic factor for 6 days. The cells which were cultured in basic culture medium were considered as control group. Morphology of differentiated cells as well as process elongation were examined by an inverted microscope. In addition, the neural differentiation markers (Nestin and MAP2) were studied employing immunocytochemistry. Neuronal-like processes appeared 8 days after treatment. Neural progenitor marker (Nestin) and a mature neural marker (MAP2) were expressed in treated group. Moreover Nissl bodies were found in the cytoplasm of treated group. Taking these together, we have designed a simple protocol for generating neuron-like cells using CSF from the hDPSCs, applicable for cell therapy in several neurodegenerative disorders including Alzheimer's disease.
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Affiliation(s)
- Ghazaleh Goudarzi
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hatef Ghasemi Hamidabadi
- Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Immunogenetic Research Center, Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Nazm Bojnordi
- Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Immunogenetic Research Center, Department of Anatomy & Cell Biology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Azim Hedayatpour
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Niapour
- Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Maria Zahiri
- Department of Anatomical Sciences, School of Medical Sciences, Bushehr University of Medical Sciences, Bushehr, Iran
| | | | - Shahram Darabi
- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
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Park BN, Kim JH, Lim TS, Park SH, Kim TG, Yoon BS, Son KS, Yoon JK, An YS. Therapeutic effect of mesenchymal stem cells in an animal model of Alzheimer's disease evaluated by β-amyloid positron emission tomography imaging. Aust N Z J Psychiatry 2020; 54:883-891. [PMID: 32436738 DOI: 10.1177/0004867420917467] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE We evaluated the effects of bone marrow-derived mesenchymal stem cells in a model of Alzheimer's disease using serial [18F]Florbetaben positron emission tomography. METHODS 3xTg Alzheimer's disease mice were treated with intravenously injected bone marrow-derived mesenchymal stem cells, and animals without stem cell therapy were used as controls. Serial [18F]Florbetaben positron emission tomography was performed after therapy. The standardized uptake value ratio was measured as the cortex standardized uptake value divided by the cerebellum standardized uptake value. Memory function and histological changes were observed using the Barnes maze test and β-amyloid-reactive cells. RESULTS Standardized uptake value ratio decreased significantly from day 14 after stem cell administration in the bone marrow-derived mesenchymal stem cells-treated group (n = 28). In contrast, there was no change in the ratio in control mice (n = 25) at any time point. In addition, mice that received bone marrow-derived mesenchymal stem cell therapy also exhibited significantly better memory function and less β-amyloid-immunopositive plaques compared to controls. CONCLUSION The therapeutic effect of intravenously injected bone marrow-derived mesenchymal stem cells in a mouse model of Alzheimer's disease was confirmed by β-amyloid positron emission tomography imaging, memory functional studies and histopathological evaluation.
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Affiliation(s)
- Bok-Nam Park
- Department of Nuclear Medicine and Molecular Imaging, School of Medicine, Ajou University, Suwon, South Korea
| | - Jang-Hee Kim
- Department of Pathology, School of Medicine, Ajou University, Suwon, South Korea
| | - Tae Sung Lim
- Department of Neurology, School of Medicine, Ajou University, Suwon, South Korea
| | - So Hyun Park
- Department of Pathology, School of Medicine, Ajou University, Suwon, South Korea
| | - Tae-Gyu Kim
- Department of Pathology, School of Medicine, Ajou University, Suwon, South Korea
| | - Bok Seon Yoon
- Neuroscience Graduate Program, Biomedical Sciences, School of Medicine, Ajou University, Suwon, South Korea
| | - Keoung Sun Son
- Neuroscience Graduate Program, Biomedical Sciences, School of Medicine, Ajou University, Suwon, South Korea
| | - Joon-Kee Yoon
- Department of Nuclear Medicine and Molecular Imaging, School of Medicine, Ajou University, Suwon, South Korea
| | - Young-Sil An
- Department of Nuclear Medicine and Molecular Imaging, School of Medicine, Ajou University, Suwon, South Korea
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Levin RA, Carnegie MH, Celermajer DS. Pulse Pressure: An Emerging Therapeutic Target for Dementia. Front Neurosci 2020; 14:669. [PMID: 32670015 PMCID: PMC7327093 DOI: 10.3389/fnins.2020.00669] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 06/02/2020] [Indexed: 12/11/2022] Open
Abstract
Elevated pulse pressure can cause blood-brain barrier dysfunction and subsequent adverse neurological changes that may drive or contribute to the development of dementia with age. In short, elevated pulse pressure dysregulates cerebral endothelial cells and increases cellular production of oxidative and inflammatory molecules. The resulting cerebral microvascular damage, along with excessive pulsatile mechanical force, can induce breakdown of the blood-brain barrier, which in turn triggers brain cell impairment and death. We speculate that elevated pulse pressure may also reduce the efficacy of other therapeutic strategies for dementia. For instance, BACE1 inhibitors and anti-amyloid-β biologics reduce amyloid-β deposits in the brain that are thought to be a cause of Alzheimer’s disease, the most prevalent form of dementia. However, upregulation of oxidative and inflammatory molecules and increased amyloid-β secretion by cerebral endothelial cells exposed to elevated pulse pressure may hinder cognitive improvements with these drugs. Additionally, stem or progenitor cell therapy has the potential to repair blood-brain barrier damage, but chronic oxidative and inflammatory stress due to elevated pulse pressure can inhibit stem and progenitor cell regeneration. Finally, we discuss current efforts to repurpose blood pressure medications to prevent or treat dementia. We propose that new drugs or devices should be developed to safely reduce elevated pulse pressure specifically to the brain. Such novel technologies may alleviate an entire downstream pathway of cellular dysfunction, oxidation, inflammation, and amyloidogenesis, thereby preventing pulse-pressure-induced cognitive decline. Furthermore, these technologies may also enhance efficacy of other dementia therapeutics when used in combination.
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Affiliation(s)
- Rachel A Levin
- The Brain Protection Company, Sydney, NSW, Australia.,M.H. Carnegie & Co., Sydney, NSW, Australia
| | - Mark H Carnegie
- The Brain Protection Company, Sydney, NSW, Australia.,M.H. Carnegie & Co., Sydney, NSW, Australia
| | - David S Celermajer
- The Brain Protection Company, Sydney, NSW, Australia.,The Heart Research Institute, Sydney, NSW, Australia
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Bi D, Wen L, Wu Z, Shen Y. GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease. Alzheimers Dement 2020; 16:1312-1329. [PMID: 32543726 DOI: 10.1002/alz.12088] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 01/28/2020] [Accepted: 02/10/2020] [Indexed: 12/28/2022]
Abstract
OBJECTIVE To propose a new hypothesis that GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease (AD). BACKGROUND Synaptic dysfunction and E/I imbalance emerge decades before the appearance of cognitive decline in AD patients, which contribute to neurodegeneration. Initially, E/I imbalance was thought to occur first, due to dysfunction of the glutamatergic and cholinergic systems. However, new evidence has demonstrated that the GABAergic system, the counterpart of E/I balance and the major inhibitory neurotransmitter system in the central nervous system, is altered enormously and that this contributes to E/I imbalance and further AD pathogenesis. NEW HYPOTHESIS Alterations to the GABAergic system, induced by multiple AD pathogenic or risk factors, contribute to E/I imbalance and AD pathogenesis. MAJOR CHALLENGES FOR THE HYPOTHESIS This GABAergic hypothesis accounts for many critical questions and common challenges confronting a new hypothesis of AD pathogenesis. More specifically, it explains why amyloid beta (Aβ), β-secretase (BACE1), apolipoprotein E4 gene (APOE ε4), hyperactive glia cells, contributes to AD pathogenesis and why age and sex are the risk factors of AD. GABAergic dysfunction promotes the spread of Aβ pathology throughout the AD brain and associated cognitive impairments, and the induction of dysfunction induced by these varied risk factors shares this common neurobiology leading to E/I imbalance. In turn, some of these factors exacerbate GABAergic dysfunction and E/I imbalance. Moreover, the GABAergic system modulates various brain functions and thus, the GABAergic hypothesis accounts for nonamnestic manifestations. Furthermore, corrections of E/I balance through manipulation of GABAergic functions have shown positive outcomes in preclinical and clinical studies, suggesting the potential of the GABAergic system as a therapeutic target in AD. LINKAGE TO OTHER MAJOR THEORIES Dysfunction of the GABAergic system is induced by multiple critical signaling pathways, which include the existing major theories of AD pathogenesis, such as the Aβ and neuroinflammation hypotheses. In a new perspective, this GABAergic hypothesis accounts for the E/I imbalance and related excitotoxicity, which contribute to cognitive decline and AD pathogenesis. Therefore, the GABAergic system could be a key target to restore, at least partially, the E/I balance and cognitive function in AD patients.
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Affiliation(s)
- Danlei Bi
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Institute on Aging and Brain Disorders, University of Sciences and Technology of China, Hefei, China.,Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lang Wen
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Institute on Aging and Brain Disorders, University of Sciences and Technology of China, Hefei, China.,Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zujun Wu
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Institute on Aging and Brain Disorders, University of Sciences and Technology of China, Hefei, China.,Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yong Shen
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Institute on Aging and Brain Disorders, University of Sciences and Technology of China, Hefei, China.,Neurodegenerative Disease Research Center, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Wang J, Hu WW, Jiang Z, Feng MJ. Advances in treatment of neurodegenerative diseases: Perspectives for combination of stem cells with neurotrophic factors. World J Stem Cells 2020; 12:323-338. [PMID: 32547681 PMCID: PMC7280867 DOI: 10.4252/wjsc.v12.i5.323] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, are a group of incurable neurological disorders, characterized by the chronic progressive loss of different neuronal subtypes. However, despite its increasing prevalence among the ever-increasing aging population, little progress has been made in the coincident immense efforts towards development of therapeutic agents. Research interest has recently turned towards stem cells including stem cells-derived exosomes, neurotrophic factors, and their combination as potential therapeutic agents in neurodegenerative diseases. In this review, we summarize the progress in therapeutic strategies based on stem cells combined with neurotrophic factors and mesenchymal stem cells-derived exosomes for neurodegenerative diseases, with an emphasis on the combination therapy.
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Affiliation(s)
- Jie Wang
- Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China
- Department of Neurology, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, Jiangsu Province, China
| | - Wei-Wei Hu
- Department of Geriatrics, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhi Jiang
- Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China
| | - Mei-Jiang Feng
- Department of Geriatrics, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu Province, China
- Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing 210011, Jiangsu Province, China.
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Abstract
Magnetic targeting (MT) has been an emerging technology which is used to improve the delivery and retention of transplanted therapeutic cells in target site over the past 20 years. Meanwhile, stem cells have also been a research hotspot in cell therapy in recent years. Several researchers have combined the MT technology with Stem cell therapy in order to improve the efficacy. However, Different types of Magnetic Nano particles (MNPs) have presented different effects, and how to choose a proper MNPs became a question. This article aims to introduce the preparation method and application field of different types of magnetic Nanoparticles, discuss the pros and cons of different types of MNPs in stem cell therapy and make a prospect of MT technology in Stem cell therapy.
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Bhute S, Sarmah D, Datta A, Rane P, Shard A, Goswami A, Borah A, Kalia K, Dave KR, Bhattacharya P. Molecular Pathogenesis and Interventional Strategies for Alzheimer's Disease: Promises and Pitfalls. ACS Pharmacol Transl Sci 2020; 3:472-488. [PMID: 32566913 DOI: 10.1021/acsptsci.9b00104] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) is a debilitating disorder characterized by age-related dementia, which has no effective treatment to date. β-Amyloid depositions and hyperphosphorylated tau proteins are the main pathological hallmarks, along with oxidative stress, N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity, and low levels of acetylcholine. Current pharmacotherapy for AD only provides symptomatic relief and limited improvement in cognitive functions. Many molecules have been explored that show promising outcomes in AD therapy and can regulate cellular survival through different pathways. To have a vivid approach to strategize the treatment regimen, AD physiopathology should be better explained considering diverse etiological factors in conjunction with biochemical disturbances. This Review attempts to discuss different disease modification approaches and address the novel therapeutic targets of AD that might pave the way for new drug discovery using the well-defined targets for therapy of the disease.
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Affiliation(s)
- Shashikala Bhute
- Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar-382355, Gujarat, India
| | - Deepaneeta Sarmah
- Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar-382355, Gujarat, India
| | - Aishika Datta
- Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar-382355, Gujarat, India
| | - Pallavi Rane
- Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar-382355, Gujarat, India
| | - Amit Shard
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar-382355, Gujarat, India
| | - Avirag Goswami
- Department of Neurology, Albert Einstein Medical Center, Philadelphia, Pennsylvania 19141, United States
| | - Anupom Borah
- Department of Life Science and Bioinformatics, Assam University, Silchar, Assam-788011, India
| | - Kiran Kalia
- Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar-382355, Gujarat, India
| | - Kunjan R Dave
- Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar-382355, Gujarat, India
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49
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Hour FQ, Moghadam AJ, Shakeri-Zadeh A, Bakhtiyari M, Shabani R, Mehdizadeh M. Magnetic targeted delivery of the SPIONs-labeled mesenchymal stem cells derived from human Wharton's jelly in Alzheimer's rat models. J Control Release 2020; 321:430-441. [PMID: 32097673 DOI: 10.1016/j.jconrel.2020.02.035] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/16/2020] [Accepted: 02/21/2020] [Indexed: 12/29/2022]
Abstract
Alzheimer's disease (AD) as a progressive neurodegenerative disorder is one of the leading causes of death globally. Among all treatment approaches, mesenchymal stem cells (MSCs)-based therapy is a promising modality for neurological disorders including the AD. This study aimed to magnetically deliver human Wharton's jelly-derived MSCs (WJ-MSCs) toward the hippocampal area within the AD rat's brain and determine the effects of them in cognitive improvement. Rats were randomly divided into five groups as follow: vehicle-treated control, AD model (injection of 8 μg/kg of amyloid β 1-42), IV-NTC (treated with IV-injected Non-Targeted Cells), IV-TC (treated with IV-injected Targeted Cells), and ICV-NTC (treated with Intracerebroventricular-injected Non-Targeted Cells). WJ-MSCs were labeled with dextran-coated superparamagnetic iron oxide nanoparticles (dex-SPIONs, 50 μg/ml), by bio-mimicry method. SPIONs-labeled MSCs were highly prussian blue positive with an intracellular iron concentration of 2.9 ± 0.08 pg/cell, which were successfully targeted into the hippocampus of AD rats by a halbach magnet array as magnetic targeted cell delivery (MTCD) technique. Presence of SPIONs-labeled cells in hippocampal area was proved by magnetic resonance imaging (MRI) in which signal intensity was reduced by increasing the number of these cells. Behavioral examinations showed that WJ-MSCs caused memory and cognitive improvement. Also, histological assessments showed functional improvement of hippocampal cells by expression of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). Overall, this study indicates MTCD approach as an alternative in MSC-based regenerative medicine because it approximately has the same results as invasive directly ICV-injection method has.
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Affiliation(s)
- Farshid Qiyami Hour
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Johari Moghadam
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Shakeri-Zadeh
- Medical Physics Department, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Bakhtiyari
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ronak Shabani
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Mehdi Mehdizadeh
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
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50
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Zhu Q, Zhang N, Hu N, Jiang R, Lu H, Xuan A, Long D, Chen Y. Neural stem cell transplantation improves learning and memory by protecting cholinergic neurons and restoring synaptic impairment in an amyloid precursor protein/presenilin 1 transgenic mouse model of Alzheimer's disease. Mol Med Rep 2020; 21:1172-1180. [PMID: 31922229 PMCID: PMC7002968 DOI: 10.3892/mmr.2020.10918] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 09/04/2019] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder. It is featured by the progressive accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles. This can eventually lead to a decrease of cholinergic neurons in the basal forebrain. Stem cell transplantation is an effective treatment for neurodegenerative diseases. Previous studies have revealed that different types of stem or progenitor cells can mitigate cognition impairment in different Alzheimer's disease mouse models. However, understanding the underlying mechanisms of neural stem cell (NSC) therapies for AD requires further investigation. In the present study, the effects and the underlying mechanisms of the treatment of AD by NSCs are reported. The latter were labelled with the enhanced green fluorescent protein (EGFP) prior to implantation into the bilateral hippocampus of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mouse model of AD. It was observed that the number of basal forebrain cholinergic neurons was restored and the expression of choline acetyltransferase (ChAT) protein was increased. Moreover, the levels of synaptophysin (SYP), postsynaptic density protein 95 (PSD-95) and microtubule-associated protein (MAP-2) were significantly increased in the hippocampus of NSC-treated AD mice. Notably, spatial learning and memory were both improved after transplantation of NSCs. In conclusion, the present study revealed that NSC transplantation improved learning and memory functions in an AD mouse model. This treatment allowed repairing of basal forebrain cholinergic neurons and increased the expression of the cognition-related proteins SYP, PSD-95 and MAP-2 in the hippocampus.
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Affiliation(s)
- Qing Zhu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
| | - Nianping Zhang
- The Teaching and Research Section of Surgery, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, P.R. China
| | - Nan Hu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
| | - Rongrong Jiang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
| | - Huicong Lu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
| | - Aiguo Xuan
- Department of Human Anatomy, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Dahong Long
- Department of Human Anatomy, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Yan Chen
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
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