Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease.
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.
Blurton-Jones
Mathew
M
Department of Neurobiology and Behavior and Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697, USA.
Kitazawa
Masashi
M
Martinez-Coria
Hilda
H
Castello
Nicholas A
NA
Müller
Franz-Josef
FJ
Loring
Jeanne F
JF
Yamasaki
Tritia R
TR
Poon
Wayne W
WW
Green
Kim N
KN
LaFerla
Frank M
FM
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
D019208:Brain-Derived Neurotrophic Factor; D016875:tau Proteins; D049452:Green Fluorescent Proteins