Targeting vulnerable microcircuits in the ventral hippocampus of male transgenic mice to rescue Alzheimer‑like social memory loss  

作　　者：Hui-Yang Lei Gui-Lin Pi Ting He Rui Xiong Jing-Ru Lv Jia-Le Liu Dong-Qin Wu Meng-Zhu Li Kun Shi Shi-Hong Li Na-Na Yu Yang Gao Hui-Ling Yu Lin-Yu Wei Xin Wang Qiu-Zhi Zhou Pei-Lin Zou Jia-Yang Zhou Ying-Zhou Liu Nai-Ting Shen Jie Yang Dan Ke Qun Wang Gong-Ping Liu Xi-Fei Yang Jian-Zhi Wang Ying Yang 

机构地区：[1]Department of Pathophysiology,School of Basic Medicine,Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China [2]Department of Traditional Chinese Medicine,the Central Hospital of Wuhan,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430014,China [3]Key Laboratory of Modern Toxicology of Shenzhen,Shenzhen Center for Disease Control and Prevention,Shenzhen 518055,Guangdong,China [4]Co‑Innovation Center of Neuroregeneration,Nantong University,Nantong 226000,Jiangsu,China

出　　处：《Military Medical Research》2025年第1期48-71,共24页军事医学研究(英文版)

基　　金：supported in part by the National Natural Science Foundation of China(91949205,82071219,82001134,31730035,81721005,and 82201584);the Hubei Provincial Key S&T Program(2018ACA142);the Guangdong Provincial Key S&T Program(2018B030336001).

摘　　要：Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer’s disease(AD),which is closely related to tau pathology and hippocampal impairment.Due to the heterogeneity of brain neurons,the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear.Therefore,further investigation is necessary.Methods:We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis,social behavioural tests,hippocampal electrophysiology,immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR.Additionally,we utilized optogenetics and administered ursolic acid(UA)via oral gavage to examine the effects of these agents on social memory in mice.Results:The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1(vCA1)under both physiological conditions and AD-like tau pathology.As tau progressively accumulated,vCA1,especially its excitatory and parvalbumin(PV)neurons,were fully filled with mislocated and phosphorylated tau(p-Tau).This finding was not observed for dorsal hippocampal CA1(dCA1).The overexpression of human tau(hTau)in excitatory and PV neurons mimicked AD-like tau accumulation,significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1.Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory.Notably,1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB(TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion:This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation.Notably,our novel findings regard

关 键 词：Alzheimer’s disease Tau protein Ventral hippocampus Social memory Ursolic acid Transcription factor EB(TFEB) 

分 类 号：R749.16[医药卫生—神经病学与精神病学]