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

• DOI: 10.1186/s40779-024-00512-z
• Publication Date: 2024-03-11T02:01:36Z
• Authors: 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
• Keywords: Memory Impairment

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