Cerebral endothelial derived exosomes abolish cognitive impairment induced by ablation of dicer in adult neural progenitor cells

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Introduction: Dicer processes precursor miRNAs into mature miRNAs. We have demonstrated that conditional knockout of Dicer (Dicer/Cko) in adult neural progenitor cells (NPCs) impairs neurogenesis and cognitive function. The present study tested the hypothesis that cerebral endothelial-derived exosomes carrying mature miRNAs promote neurogenesis and improve cognitive function by communication with NPCs in Dicer/Cko mice. Methods and Results: Exosomes harvested from cultured cerebral endothelial cells (CEC-Ex, 1x109 exosomes) were intranasally administered twice a week for two consecutive weeks into mice (n=10) with conditional ablation of Dicer (Dicer/Cko) in NPCs (Ascl1-CreER:Dicerflox/flox). Dicer/Cko mice treated with saline (n=12) were used as control. Cognitive tests were performed, including Morris Water Maze (MWM) for hippocampal related learning and memory, odor-based novelty recognition for olfactory memory, and social interaction for memory of interactions with novel conspecifics. Compared to wild-type mice,Dicer/Cko mice treated with saline exhibited substantial cognitive impairment. The CEC-Ex treatment diminished cognitive deficits and these mice exhibited an increase of 40% more time spent in the correct quadrant (p<0.05) of the MWM, and increased time exploring new odor objects (71±9% vs 41 ±10% saline, p<0.05) and increased time in contact with a strange mouse during the sociability test. Using a Cre/flox reporter approach, we found that the exosomes carrying Cre mRNA entered NPCs in the subventricular zone (SVZ) and dentate gyrus (DG). The CEC-Ex treatment significantly (p<0.05) increased BrdU NPCs (20 ± 1% vs 14 ± 2%, SVZ, 16±1% vs 12±3%, DG ) and DCX+ neuroblasts (27 ± 2% vs 22 ± 3%, SVZ, 33 ± 2% vs 25 ± 3%, DG), and reduced apoptotic cells by more than 50% in these two areas. RT-PCR analysis showed that Dicer/Cko mice exhibited substantial reduction of mature miRNAs that regulate neurogenesis including miR-124, -146a and -17-92 cluster in NPCs, whereas the CEC-Ex treatment increased these mature miRNAs in Dicer/Cko NPCs. Conclusion: The CEC-Ex can reverse impaired neurogenesis and cognitive function induced by ablation of Dicer, which is likely attributed to the delivery of mature miRNAs into NPCs by CEC-Ex.




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