title: Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease.
abstract: Neural stem cell (NSC) transplantation represents an unexplored approach for treating neurodegenerative disorders associated with cognitive decline such as Alzheimer disease (AD). Here, we used aged triple transgenic mice (3xTg-AD) that express pathogenic forms of amyloid precursor protein, presenilin, and tau to investigate the effect of neural stem cell transplantation on AD-related neuropathology and cognitive dysfunction. Interestingly, despite widespread and established Ass plaque and neurofibrillary tangle pathology, hippocampal neural stem cell transplantation rescues the spatial learning and memory deficits in aged 3xTg-AD mice. Remarkably, cognitive function is improved without altering Ass or tau pathology. Instead, the mechanism underlying the improved cognition involves a robust enhancement of hippocampal synaptic density, mediated by brain-derived neurotrophic factor (BDNF). Gain-of-function studies show that recombinant BDNF mimics the beneficial effects of NSC transplantation. Furthermore, loss-of-function studies show that depletion of NSC-derived BDNF fails to improve cognition or restore hippocampal synaptic density. Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF.
authors.affiliation: Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
authors.forename: Hilda
authors.initials: H
authors.lastname: Martinez-Coria
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Castello
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Müller
authors.forename: Jeanne F
authors.initials: JF
authors.lastname: Loring
authors.forename: Tritia R
authors.initials: TR
authors.lastname: Yamasaki
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002633:Chemotaxis; D003071:Cognition; D003072:Cognition Disorders / Q000473:pathology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016875:tau Proteins; D049452:Green Fluorescent Proteins