title: Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer's disease and neuronal loss.
abstract: Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, affecting over 35 million people worldwide. Pathologically, AD is characterized by the progressive accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles within the brain. Together, these pathologies lead to marked neuronal and synaptic loss and corresponding impairments in cognition. Current treatments, and recent clinical trials, have failed to modify the clinical course of AD; thus, the development of novel and innovative therapies is urgently needed. Over the last decade, the potential use of stem cells to treat cognitive impairment has received growing attention. Specifically, neural stem cell transplantation as a treatment for AD offers a novel approach with tremendous therapeutic potential. We previously reported that intrahippocampal transplantation of murine neural stem cells (mNSCs) can enhance synaptogenesis and improve cognition in 3xTg-AD mice and the CaM/Tet-DT(A) model of hippocampal neuronal loss. These promising findings prompted us to examine a human neural stem cell population, HuCNS-SC, which has already been clinically tested for other neurodegenerative disorders. In this study, we provide the first evidence that transplantation of research grade HuCNS-SCs can improve cognition in two complementary models of neurodegeneration. We also demonstrate that HuCNS-SC cells can migrate and differentiate into immature neurons and glia and significantly increase synaptic and growth-associated markers in both 3xTg-AD and CaM/Tet-DTA mice. Interestingly, improvements in aged 3xTg-AD mice were not associated with altered Aβ or tau pathology. Rather, our findings suggest that human NSC transplantation improves cognition by enhancing endogenous synaptogenesis. Taken together, our data provide the first preclinical evidence that human NSC transplantation could be a safe and effective therapeutic approach for treating AD.
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California.
authors.forename: Rahasson R
authors.initials: RR
authors.lastname: Ager
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California.|Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, California.
authors.forename: Joy L
authors.initials: JL
authors.lastname: Davis
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California.|Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, California.
authors.forename: Andy
authors.initials: A
authors.lastname: Agazaryan
authors.affiliation: Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, California.
authors.forename: Francisca
authors.initials: F
authors.lastname: Benavente
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California.|Department of Neurobiology and Behavior, University of California, Irvine, California.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California.|Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, California.|Department of Neurobiology and Behavior, University of California, Irvine, California.
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California.|Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, California.|Department of Neurobiology and Behavior, University of California, Irvine, California.
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D003072:Cognition Disorders / Q000209:etiology* / Q000601:surgery*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D058953:Neural Stem Cells / Q000502:physiology / Q000637:transplantation*; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000473:pathology*; D013569:Synapses / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D016875:tau Proteins
keywords: Alzheimer's disease; immune suppression; neural stem cells; therapeutic; transplantation