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Neural Stem Cells Rescue Cognitive and Motor Dysfunction in a Transgenic Model of Dementia with Lewy Bodies through a BDNF-Dependent Mechanism.

Abstract
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.
AuthorsNatalie R S Goldberg, Jacqueline Caesar, Ashley Park, Shawn Sedgh, Gilana Finogenov, Eliezer Masliah, Joy Davis, Mathew Blurton-Jones
JournalStem cell reports (Stem Cell Reports) Vol. 5 Issue 5 Pg. 791-804 (Nov 10 2015) ISSN: 2213-6711 [Electronic] United States
PMID26489892 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Brain-Derived Neurotrophic Factor
  • alpha-Synuclein
  • Glutamic Acid
  • Dopamine
Topics
  • Animals
  • Brain-Derived Neurotrophic Factor (genetics, metabolism)
  • Cells, Cultured
  • Cognition
  • Corpus Striatum (cytology)
  • Dopamine (metabolism)
  • Glutamic Acid (metabolism)
  • Lewy Body Disease (genetics, therapy)
  • Locomotion
  • Mice
  • Mice, Inbred C57BL
  • Neural Stem Cells (cytology, metabolism, transplantation)
  • alpha-Synuclein (genetics)

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