Hippocampal neural stem cell exosomes promote brain resilience against the impact of tau oligomers.

A promising therapeutic intervention for preventing the onset and progression of Alzheimer's Disease (AD) is to protect and improve synaptic resilience, a well-established early vulnerability associated with the toxic effects of oligomers of Aβ (AβO) and Tau (TauO). We have previously reported that exosomes from hippocampal neural stem cells (NSCs) protect synapses against AβO. Here, we demonstrate how exosomes can also shield against TauO toxicity in adult mice synapses, potentially benefiting primary and secondary tauopathies. Exosomes from hippocampal NSCs (NSCexo) or mature neurons (MNexo) were delivered intracerebroventricularly to adult wildtype male mice (C57Bl6/J). After 24 hours, TauO were administered to suppress long-term potentiation (LTP) and memory, measured by electrophysiology and contextual memory deficits measured using novel object recognition (NOR) test. We also assessed TauO binding to synapses using isolated synaptosomes and cultured hippocampal neurons. Furthermore, mimics of select miRNAs present in NSCexo, were delivered ICV to mice prior to assessment of TauO-induced suppression of hippocampal LTP. Our results showed that NSC-, not MN-, derived exosomes, prevented TauO-induced memory impairment, LTP suppression, and reduced Tau accumulation and TauO internalization in synaptosomes. These findings suggest that NSC-derived exosomes can protect against synaptic dysfunction and memory deficits induced by both AβO and TauO, offering a novel therapeutic strategy for multiple neurodegenerative states.Significance Statement NSCexo provide an unprecedented therapeutic strategy targeting an early vulnerability driven by amyloidogenic toxic oligomers associated with multiple neurodegenerative states.