Impact of neural stem cell-derived extracellular vesicles on mitochondrial dysfunction, sirtuin 1 level, and synaptic deficits in Alzheimer's disease.

Small extracellular vesicles (EVs), including exosomes, play multiple physiological roles. In neurodegenerative diseases, EVs can be pivotal in dispersing neuropathogenic proteins. This study investigates the role of neural stem cell (NSC)-derived EVs in a transgenic (Tg) mouse model of Alzheimer's disease (AD). Five weeks following treatment on 9-month-old APP/PS1 mice, the effects of NSC-derived EVs on cognitive behavior, mitochondrial function, sirtuin1 (SIRT1), synaptic function and morphology, quantification of amyloid-β (Aβ) level, and inflammatory response were investigated. The results showed that mice in the Tg-NSCs-ev group exhibited significant improvement in cognitive performance compared with Tg-Veh group. Furthermore, the expression of mitochondrial function-related factors (peroxisome proliferator-activated receptor-γ coactivator-1α [PGC1α], nuclear respiratory factor 1 and 2 [NRF1 and 2], and fission 1 [Fis1]), SIRT1 as well as synaptic proteins (growth-associated protein 43 [GAP43], synaptophysin [SYP], post-synaptic density 95 [PSD95] and microtubule-associated protein 2 [MAP2]) were significantly higher in the Tg-NSCs-ev group, when compared with the Tg-Veh group. In addition, oxidative damage markers (anti-4-Hydroxynonenal [4-HNE] and anti-3 nitrotyrosine [3-NT]), inflammatory cytokines and the microglial marker (Iba1) were significantly lower in the Tg-NSCs-ev group, compared to the Tg-Veh group. Moreover, synaptic morphology was distinctly improved in the Tg-NSCs-ev group, whereas the Aβ level was not altered. Our study provides novel evidences that NSC-derived EVs enhanced mitochondrial function, SIRT1 activation, synaptic activity, decreased inflammatory response, and rescued cognitive deficits in AD like mice.