Stem Cell Therapy for Alzheimer’s Disease: A Scoping Review for 2017–2022

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.

[1]  Jihwan Song,et al.  Mitochondrial genome mutations and neuronal dysfunction of induced pluripotent stem cells derived from patients with Alzheimer's disease , 2022, Cell proliferation.

[2]  Zhuangzhuang Xiao,et al.  Stem cells from human exfoliated deciduous teeth relieves Alzheimer's disease symptoms in SAMP8 mice by up-regulating the PPARγ pathway. , 2022, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[3]  A. Villarroel,et al.  Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer’s Disease: Possible Therapeutic Role of KV1.3 Channel Blockade , 2022, Frontiers in Cellular Neuroscience.

[4]  Juryun Kim,et al.  Mitigating Effect of Estrogen in Alzheimer’s Disease-Mimicking Cerebral Organoid , 2022, Frontiers in Neuroscience.

[5]  E. Cho,et al.  Membrane-Free Stem Cells and Pyridoxal 5′-Phosphate Synergistically Enhance Cognitive Function in Alzheimer’s Disease Mouse Model , 2022, Antioxidants.

[6]  Jingjing Xu,et al.  Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology , 2022, Journal of Neuroinflammation.

[7]  Y. Zhang,et al.  Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential , 2022, Translational neurodegeneration.

[8]  H. Ulrich,et al.  Distinct Effects of the Hippocampal Transplantation of Neural and Mesenchymal Stem Cells in a Transgenic Model of Alzheimer’s Disease , 2021, Stem Cell Reviews and Reports.

[9]  Zhenzhen Quan,et al.  Neural stem cell transplantation alleviates functional cognitive deficits in a mouse model of tauopathy , 2021, Neural regeneration research.

[10]  O. Kim,et al.  Extracellular Vesicles Released from Neprilysin Gene-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cell Enhance Therapeutic Effects in an Alzheimer's Disease Animal Model , 2021, Stem cells international.

[11]  Y. Bian,et al.  Stem cells from human exfoliated deciduous teeth affect mitochondria and reverse cognitive decline in a senescence-accelerated mouse prone 8 model. , 2021, Cytotherapy.

[12]  Young Hee Jung,et al.  Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase I clinical trial , 2021, Alzheimer's research & therapy.

[13]  Salwa,et al.  Engrafted stem cell therapy for Alzheimer's disease: A promising treatment strategy with clinical outcome. , 2021, Journal of controlled release : official journal of the Controlled Release Society.

[14]  Weiping Liu,et al.  Tail-vein injection of MSC-derived small extracellular vesicles facilitates the restoration of hippocampal neuronal morphology and function in APP / PS1 mice , 2021, Cell death discovery.

[15]  M. Aboul-Soud,et al.  Induced Pluripotent Stem Cells (iPSCs)—Roles in Regenerative Therapies, Disease Modelling and Drug Screening , 2021, Cells.

[16]  Jung Ho Jeon,et al.  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 , 2021, Stem Cell Research & Therapy.

[17]  A. Wilber,et al.  Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer's disease-like phenotypes in a preclinical mouse model , 2021, Theranostics.

[18]  S. Belemkar,et al.  An update on Alzheimer's disease: Immunotherapeutic agents, stem cell therapy and gene editing. , 2021, Life sciences.

[19]  B. Niu,et al.  Mesenchymal stem cell therapies for Alzheimer’s disease: preclinical studies , 2021, Metabolic Brain Disease.

[20]  C. Soto,et al.  Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer’s Disease , 2021, Cells.

[21]  Ren-Shyan Liu,et al.  Mesenchymal Stem Cell-Derived Exosomes Ameliorate Alzheimer’s Disease Pathology and Improve Cognitive Deficits , 2021, Biomedicines.

[22]  H. Cui,et al.  Induced pluripotent stem cells derived from one 70-years-old male donor with the APOE-ε4/ε4 alleles. , 2021, Stem cell research.

[23]  Jui-Ti Ma,et al.  Mesenchymal stem cell‐conditioned medium attenuates the retinal pathology in amyloid‐β‐induced rat model of Alzheimer's disease: Underlying mechanisms , 2021, Aging cell.

[24]  E. Mayo-Wilson,et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews , 2021, BMJ.

[25]  J. Hare,et al.  Intravenous administration of mesenchymal stem cells reduces Tau phosphorylation and inflammation in the 3xTg-AD mouse model of Alzheimer's disease , 2021, Experimental Neurology.

[26]  Fen Wang,et al.  Intranasal Transplantation of Human Neural Stem Cells Ameliorates Alzheimer's Disease-Like Pathology in a Mouse Model , 2021, Frontiers in Aging Neuroscience.

[27]  J. Baulch,et al.  Human neural stem cell-derived extracellular vesicles mitigate hallmarks of Alzheimer’s disease , 2021, Alzheimer's Research & Therapy.

[28]  Zefeng Wang,et al.  SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc- SMPDL3B , 2021, bioRxiv.

[29]  Han Liu,et al.  Generation of induced pluripotent stem cell line (ZZUi0024-A) from a 51-year-old patient with APP gene mutation in Alzheimer' s disease. , 2021, Stem cell research.

[30]  X. Yang,et al.  A Nanoformulation‐Mediated Multifunctional Stem Cell Therapy with Improved Beta‐Amyloid Clearance and Neural Regeneration for Alzheimer's Disease , 2021, Advanced materials.

[31]  Saeid Bagheri-Mohammadi.  Stem cell-based therapy as a promising approach in Alzheimer's disease: current perspectives on novel treatment , 2021, Cell and Tissue Banking.

[32]  Wei Li,et al.  Therapeutic potential of dental pulp stem cell transplantation in a rat model of Alzheimer’s disease , 2020, Neural regeneration research.

[33]  Jinlan Jiang,et al.  Fe3O4@polydopamine nanoparticle-loaded human umbilical cord mesenchymal stem cells improve the cognitive function in Alzheimer's disease mice by promoting hippocampal neurogenesis. , 2020, Nanomedicine : nanotechnology, biology, and medicine.

[34]  Li-Ru Zhao,et al.  Reparative Effects of Stem Cell Factor and Granulocyte Colony-Stimulating Factor in Aged APP/PS1 Mice , 2020, Aging and disease.

[35]  David A. Brafman,et al.  APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids , 2020, Nature Communications.

[36]  Chen Xu,et al.  Mesenchymal Stem Cell-Conditioned Medium Improves Mitochondrial Dysfunction and Suppresses Apoptosis in Okadaic Acid-Treated SH-SY5Y Cells by Extracellular Vesicle Mitochondrial Transfer. , 2020, Journal of Alzheimer's disease : JAD.

[37]  Mei Xu,et al.  Human Induced Pluripotent Stem Cell-Derived Neural Cells from Alzheimer's Disease Patients Exhibited Different Susceptibility to Oxidative Stress. , 2020, Stem cells and development.

[38]  P. Lei,et al.  Mesenchymal stem cell-derived exosome: a promising alternative in the therapy of Alzheimer’s disease , 2020, Alzheimer's Research & Therapy.

[39]  S. Simorgh,et al.  Human adipose-derived stem cells reduce receptor-interacting protein 1, receptor-interacting protein 3, and mixed lineage kinase domain-like pseudokinase as necroptotic markers in rat model of Alzheimer's disease , 2020, Indian journal of pharmacology.

[40]  Min Su,et al.  Administration of Amyloid Precursor Protein Gene Deleted Mouse ESC-Derived Thymic Epithelial Progenitors Attenuates Alzheimer's Pathology , 2020, Frontiers in Immunology.

[41]  Jian Zhao,et al.  Generation of an induced pluripotent stem cell line (SIAISi003-A) from a 79-year-old patient with Alzheimer's disease having APOE3/4 genetic background. , 2020, Stem cell research.

[42]  D. Bennett,et al.  Author response: Healthy lifestyle and the risk of Alzheimer dementia: Findings from 2 longitudinal studies , 2020 .

[43]  Seulah Lee,et al.  Mesenchymal Stem Cell Therapy and Alzheimer's Disease: Current Status and Future Perspectives. , 2020, Journal of Alzheimer's disease : JAD.

[44]  G. Forloni,et al.  Intranasal delivery of mesenchymal stem cell secretome repairs the brain of Alzheimer’s mice , 2020, Cell Death & Differentiation.

[45]  M. Fujimiya,et al.  Bone marrow-derived mesenchymal stem cells improve cognitive impairment in an Alzheimer’s disease model by increasing the expression of microRNA-146a in hippocampus , 2020, Scientific Reports.

[46]  P. Lee,et al.  Feasibility and Efficacy of Intra-Arterial Administration of Embryonic Stem Cell Derived-Mesenchymal Stem Cells in Animal Model of Alzheimer's Disease. , 2020, Journal of Alzheimer's disease : JAD.

[47]  J. Brewer,et al.  Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. , 2020, JAMA neurology.

[48]  Yun-Bae Kim,et al.  Human Neural Stem Cells Encoding ChAT Gene Restore Cognitive Function via Acetylcholine Synthesis, Aβ Elimination, and Neuroregeneration in APPswe/PS1dE9 Mice , 2020, International journal of molecular sciences.

[49]  C. Qin,et al.  Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology in animal models of Alzheimer’s disease: a meta-analytic review on potential mechanisms , 2020, Translational Neurodegeneration.

[50]  K. Mortezaee,et al.  Therapeutic effects of melatonin-treated bone marrow mesenchymal stem cells (BMSC) in a rat model of Alzheimer's disease , 2020, Journal of Chemical Neuroanatomy.

[51]  Joon-Kee Yoon,et al.  Therapeutic effect of mesenchymal stem cells in an animal model of Alzheimer’s disease evaluated by β-amyloid positron emission tomography imaging , 2020, The Australian and New Zealand journal of psychiatry.

[52]  A. Mamun,et al.  Combination Drug Therapy for the Management of Alzheimer’s Disease , 2020, International journal of molecular sciences.

[53]  I. Vietor,et al.  Mesenchymal stem cells could be considered as a candidate for further studies in cell-based therapy of Alzheimer's disease via targeting the signaling pathways. , 2020, ACS chemical neuroscience.

[54]  Hui Chen,et al.  Mesenchymal stem cell-derived exosomal miR-223 regulates neuronal cell apoptosis , 2020, Cell Death & Disease.

[55]  H. Harn,et al.  Induced Pluripotent Stem Cell (iPSC)-Based Neurodegenerative Disease Models for Phenotype Recapitulation and Drug Screening , 2020, Molecules.

[56]  M. Sabbagh,et al.  Alzheimer’s Disease Drug Development Pipeline 2020 , 2020, The Journal of Prevention of Alzheimer's Disease.

[57]  Hongmin Wang,et al.  Disrupted blood-brain barrier in 5×FAD mouse model of Alzheimer's disease can be mimicked and repaired in vitro with neural stem cell-derived exosomes. , 2020, Biochemical and biophysical research communications.

[58]  H. Harn,et al.  Human-Induced Pluripotent Stem Cells and Herbal Small-Molecule Drugs for Treatment of Alzheimer’s Disease , 2020, International journal of molecular sciences.

[59]  K. Tsai,et al.  Effects of neural stem cell transplantation in Alzheimer’s disease models , 2020, Journal of Biomedical Science.

[60]  K. Tsai,et al.  Effects of neural stem cell transplantation in Alzheimer’s disease models , 2020, Journal of Biomedical Science.

[61]  A. Xuan,et al.  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 , 2020, Molecular medicine reports.

[62]  S. Mehrabadi,et al.  Hypoxic-conditioned medium from adipose tissue mesenchymal stem cells improved neuroinflammation through alternation of toll like receptor (TLR) 2 and TLR4 expression in model of Alzheimer's disease rats , 2019, Behavioural Brain Research.

[63]  M. I. Coşacak,et al.  Alzheimer’s disease, neural stem cells and neurogenesis: cellular phase at single-cell level , 2019, Neural regeneration research.

[64]  S. Khoshnam,et al.  Human Pluripotent Stem Cells in Neurodegenerative Diseases: Potentials, Advances, and Limitations. , 2020, Current stem cell research & therapy.

[65]  K. Cheung,et al.  Mitochondrial calcium signaling as a therapeutic target for Alzheimer's disease. , 2019, Current Alzheimer research.

[66]  M. Hamblin,et al.  Neural stem cell therapy for neurovascular injury in Alzheimer's disease , 2019, Experimental Neurology.

[67]  M. Lo Giudice,et al.  Calcilytic NPS 2143 Reduces Amyloid Secretion and Increases sAβPPα Release from PSEN1 Mutant iPSC-Derived Neurons , 2019, Journal of Alzheimer's disease : JAD.

[68]  U. Gómez-Pinedo,et al.  Mesenchymal stem cell-derived exosomes promote neurogenesis and cognitive function recovery in a mouse model of Alzheimer’s disease , 2019, Neural regeneration research.

[69]  D. Praticò,et al.  Impaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease , 2019, Nature Communications.

[70]  G. Bu,et al.  Differential Effects of Extracellular Vesicles of Lineage-Specific Human Pluripotent Stem Cells on the Cellular Behaviors of Isogenic Cortical Spheroids , 2019, Cells.

[71]  M. Yousefi,et al.  Prospects for the application of mesenchymal stem cells in Alzheimer's disease treatment. , 2019, Life sciences.

[72]  Robert R Butler Iii,et al.  The Genetic Relevance of Human Induced Pluripotent Stem Cell-Derived Microglia to Alzheimer’s Disease and Major Neuropsychiatric Disorders , 2019, Molecular Neuropsychiatry.

[73]  E. Nasiri,et al.  Melatonin-pretreated adipose-derived mesenchymal stem cells efficeintly improved learning, memory, and cognition in an animal model of Alzheimer's disease , 2019, Metabolic Brain Disease.

[74]  Meijiang Feng,et al.  Brain-derived neurotrophic factor modified human umbilical cord mesenchymal stem cells-derived cholinergic-like neurons improve spatial learning and memory ability in Alzheimer’s disease rats , 2019, Brain Research.

[75]  Jiesi Luo,et al.  The potential and limitations of induced pluripotent stem cells to achieve wound healing , 2019, Stem Cell Research & Therapy.

[76]  J. Power,et al.  Alzheimer’s Disease and Cancer: When Two Monsters Cannot Be Together , 2019, Front. Neurosci..

[77]  L. Goldstein,et al.  Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer’s Disease Neurons , 2019, Cell stem cell.

[78]  I. Amiri,et al.  Dimethyloxalylglycine preconditioning enhances protective effects of bone marrow-derived mesenchymal stem cells in Aβ- induced Alzheimer disease , 2019, Physiology & Behavior.

[79]  G. Church,et al.  REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer’s Disease , 2019, Cell reports.

[80]  L. Mohamet,et al.  Induced Pluripotent Stem Cell-Derived Astroglia: A New Tool for Research Towards the Treatment of Alzheimer's Disease. , 2019, Advances in experimental medicine and biology.

[81]  Changhe Shi,et al.  Generation of induced pluripotent stem cell line (ZZUi0013-A) from a 65-year-old patient with a novel MEOX2 gene mutation in Alzheimer's disease. , 2019, Stem cell research.

[82]  M. Alipour,et al.  Stem cell therapy in Alzheimer’s disease: possible benefits and limiting drawbacks , 2019, Molecular Biology Reports.

[83]  J. Bi,et al.  Anti-inflammatory effects of bone marrow mesenchymal stem cells on mice with Alzheimer's disease , 2018, Experimental and therapeutic medicine.

[84]  E. Feldman,et al.  Human neural stem cell transplantation improves cognition in a murine model of Alzheimer’s disease , 2018, Scientific Reports.

[85]  S. Agatonovic-Kustrin,et al.  A molecular approach in drug development for Alzheimer's disease. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[86]  Kuo-Hsuan Chang,et al.  Modeling Alzheimer’s Disease by Induced Pluripotent Stem Cells Carrying APP D678H Mutation , 2018, Molecular Neurobiology.

[87]  J. Yee,et al.  A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration , 2018, bioRxiv.

[88]  Reza Salarinia,et al.  Stem cell‐ and gene‐based therapies as potential candidates in Alzheimer's therapy , 2018, Journal of cellular biochemistry.

[89]  E. Cano,et al.  Neuronal and Glial Differentiation of Human Neural Stem Cells Is Regulated by Amyloid Precursor Protein (APP) Levels , 2018, Molecular Neurobiology.

[90]  L. Tsai,et al.  APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types , 2018, Neuron.

[91]  H. Feng,et al.  Umbilical Cord Mesenchymal Stem Cells Conditioned Medium Promotes Aβ25-35 phagocytosis by Modulating Autophagy and Aβ-Degrading Enzymes in BV2 Cells , 2018, Journal of Molecular Neuroscience.

[92]  Ruiyi Zhang,et al.  MicroRNA Let-7f-5p Promotes Bone Marrow Mesenchymal Stem Cells Survival by Targeting Caspase-3 in Alzheimer Disease Model , 2018, Front. Neurosci..

[93]  Seung-Pyo Lee,et al.  Current Perspectives regarding Stem Cell-Based Therapy for Alzheimer's Disease , 2018, Stem cells international.

[94]  Xinxin Wang,et al.  Resveratrol promotes hUC-MSCs engraftment and neural repair in a mouse model of Alzheimer’s disease , 2018, Behavioural Brain Research.

[95]  M. Stojkovic,et al.  Ethical and Safety Issues of Stem Cell-Based Therapy , 2018, International journal of medical sciences.

[96]  Weiping Liu,et al.  Upregulation of seladin-1 and nestin expression in bone marrow mesenchymal stem cell transplantation via the ERK1/2 and PI3K/Akt signaling pathways in an Alzheimer's disease model. , 2017, Oncology letters.

[97]  SoJung Lee,et al.  sRAGE prolonged stem cell survival and suppressed RAGE-related inflammatory cell and T lymphocyte accumulations in an Alzheimer's disease model. , 2018, Biochemical and biophysical research communications.

[98]  Zhenfu Wang,et al.  Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppresses iNOS Expression and Ameliorates Neural Impairment in Alzheimer's Disease Mice. , 2018, Journal of Alzheimer's disease : JAD.

[99]  X. Wen,et al.  Establishment of induced pluripotent stem cell line (ZZUi009-A) from an Alzheimer's disease patient carrying a PSEN1 gene mutation. , 2018, Stem cell research.

[100]  D. Na,et al.  Lowering the concentration affects the migration and viability of intracerebroventricular-delivered human mesenchymal stem cells. , 2017, Biochemical and biophysical research communications.

[101]  Thomas Duncan,et al.  Alzheimer’s disease, dementia, and stem cell therapy , 2017, Stem Cell Research & Therapy.

[102]  E. Mazzon,et al.  Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis , 2017, Journal of Cellular Biochemistry.

[103]  J. C. Torre,et al.  Treating cognitive impairment with transcranial low level laser therapy. , 2017, Journal of photochemistry and photobiology. B, Biology.

[104]  W. Cao,et al.  Human umbilical cord mesenchymal stem cells transplantation improves cognitive function in Alzheimer’s disease mice by decreasing oxidative stress and promoting hippocampal neurogenesis , 2017, Behavioural Brain Research.

[105]  T. Bolmont,et al.  Administrations of human adult ischemia-tolerant mesenchymal stem cells and factors reduce amyloid beta pathology in a mouse model of Alzheimer's disease , 2017, Neurobiology of Aging.

[106]  Avijit Banik,et al.  Potential for Stem Cells Therapy in Alzheimer's Disease: Do Neurotrophic Factors Play Critical Role? , 2017, Current Alzheimer research.

[107]  T. Wisniewski,et al.  Human Umbilical Cord Stem Cell Xenografts Improve Cognitive Decline and Reduce the Amyloid Burden in a Mouse Model of Alzheimer's Disease. , 2016, Current Alzheimer research.

[108]  Song Li,et al.  Induced pluripotent stem cells in Alzheimer’s disease: applications for disease modeling and cell-replacement therapy , 2016, Molecular Neurodegeneration.

[109]  G. E. Vates,et al.  Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review , 2016, International journal of molecular sciences.

[110]  Y. Takagi.  History of Neural Stem Cell Research and Its Clinical Application , 2016, Neurologia medico-chirurgica.

[111]  N. Inestrosa,et al.  Signaling pathway cross talk in Alzheimer’s disease , 2014, Cell Communication and Signaling.

[112]  G. A. de Souza,et al.  The Use of Herbal Medicine in Alzheimer's Disease—A Systematic Review , 2006, Evidence-based complementary and alternative medicine : eCAM.

[113]  E. Stopa,et al.  Basic fibroblast growth factor in Alzheimer's disease. , 1990, Biochemical and biophysical research communications.