Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer's disease
Bo Li, Yujie Chen, Yan Zhou, Xuanran Feng, Guojun Gu, Shuang Han, Nianhao Cheng, Yawen Sun, Yiming Zhang, Jiahui Cheng, Qi Zhang, Wei Zhang, Jianhui Liu
Abstract
Abstract JOURNAL/nrgr/04.03/01300535-202407000-00040/figure1/v/2026-05-11T120643Z/r/image-tiff Mitochondrial dysfunction is a hallmark of Alzheimer's disease. We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of APP/PS1 mice. Because Alzheimer's disease affects the entire brain, further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole. Here, we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing, immunostaining, and lightsheet imaging to clarify their spatial distribution. Additionally, to clarify whether the sirtuin 1 (SIRT1)-related pathway plays a regulatory role in neural stem cell-derived exosomes interfering with mitochondrial functional changes, we generated a novel nervous system-SIRT1 conditional knockout APP/PS1 mouse model. Our findings demonstrate that neural stem cell-derived exosomes significantly increase SIRT1 levels, enhance the production of mitochondrial biogenesis-related factors, and inhibit astrocyte activation, but do not suppress amyloid-β production. Thus, neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer's disease that activates the SIRT1-PGC1α signaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis. In addition, we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer's disease, and that neural stem cell-derived exosome treatment can reverse this effect, indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.