Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer's disease  

作　　者：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 

机构地区：[1]Department of Radiology,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China [2]Morphology and Spatial Multi-Omics Technology Platform,Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences,Shanghai,China [3]Department of Anesthesiology,Tongji Hospital,School of Medicine,Tongji University,Shanghai,China [4]Department of Blood Transfusion,Huashan Hospital,Fudan University,Shanghai,China

出　　处：《Neural Regeneration Research》2024年第7期1593-1601,共9页中国神经再生研究（英文版）

基　　金：supported by the National Natural Science Foundation of China,Nos.82171194 and 81974155(both to JL);the Shanghai Municipal Science and Technology Commission Medical Guide Project,No.16411969200(to WZ);Shanghai Municipal Science and Technology Commission Biomedical Science and Technology Project,No.22S31902600(to JL)。

摘　　要：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 AP P/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-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling 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.

关 键 词：Alzheimer’s disease mitochondrial biogenesis neural stem cell-derived exosome SIRT1-PGC1α regional brain distribution whole brain clearing and imaging 

分 类 号：R749.16[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]