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

摘要

Summary 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.