Neural Stem Cells Rescue Cognitive and Motor Dysfunction in a Transgenic Model of Dementia with Lewy Bodies through a BDNF-Dependent Mechanism.
Accumulation of α-synuclein (α-syn) into insoluble aggregates occurs in several related disorders collectively referred to as synucleinopathies. To date, studies have used neural stem cells (NSCs) to examine questions about α-syn propagation, but have overlooked the therapeutic potential of NSC transplantation to modulate cognition in disorders such as dementia with Lewy bodies or Parkinson's disease dementia. Here, we show that striatal transplantation of NSCs into aged α-syn transgenic mice significantly improves performance in multiple cognitive and motor domains. This recovery is associated with NSC expression of brain-derived neurotrophic factor (BDNF), which restores depleted levels and modulates dopaminergic and glutamatergic systems. Most importantly, transplantation of BDNF-depleted NSCs fails to improve behavior, whereas AAV-mediated BDNF delivery mimics the benefits of NSC transplantation, supporting a critical role for this neurotrophin in functional improvement. Thus, NSC transplantation could offer a promising approach to treat the understudied yet devastating cognitive components of many synucleinopathies.
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA; Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
Natalie R S
NRS
Goldberg
Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
Jacqueline
J
Caesar
Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
Ashley
A
Park
Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
Shawn
S
Sedgh
Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
Gilana
G
Finogenov
Department of Pathology and Medicine, University of California, San Diego, San Diego, CA 92093, USA.
Eliezer
E
Masliah
Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
Joy
J
Davis
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA; Sue & Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: mblurton@uci.edu.
Mathew
M
Blurton-Jones
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003071:Cognition; D003342:Corpus Striatum / Q000166:cytology; D004298:Dopamine / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D020961:Lewy Body Disease / Q000235:genetics / Q000628:therapy*; D008124:Locomotion; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D051844:alpha-Synuclein / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D051844:alpha-Synuclein; D018698:Glutamic Acid; D004298:Dopamine