Medial septum tau accumulation induces spatial memory deficit via disrupting medial septum–hippocampus cholinergic pathway

作者：Dongqin Wu, Di Gao, Haitao Yu, Guilin Pi, Rui Xiong, Huiyang Lei, Xin Wang, Enjie Liu, Jinwang Ye, Huilin Yu, Yang Gao, Ting He, Tao Jiang, Fei Sun, Jingfen Su, Guoda Song, Wenju Peng, Ying Yang, Jian‐Zhi Wang · 发表于：Clinical and Translational Medicine · 年份：2021 · DOI：10.1002/ctm2.428 · 被引用次数：40 · 研究领域：Alzheimer's disease research and treatments、Cholinesterase and Neurodegenerative Diseases、Neuroscience and Neuropharmacology Research

Abstract Tau accumulation and cholinergic impairment are characteristic pathologies in Alzheimer's disease (AD). However, the causal role of tau accumulation in cholinergic lesion is elusive. Here, we observed an aberrant tau accumulation in the medial septum (MS) of 3xTg and 5xFAD mice, especially in their cholinergic neurons. Overexpressing hTau in mouse MS (MS hTau ) for 6 months but not 3 months induced spatial memory impairment without changing object recognition and anxiety‐like behavior, indicating a specific and time‐dependent effect of MS‐hTau accumulation on spatial cognitive functions. With increasing hTau accumulation, the MS hTau mice showed a time‐dependent cholinergic neuron loss with reduced cholinergic projections to the hippocampus. Intraperitoneal administration of donepezil, a cholinesterase inhibitor, for 1 month ameliorated the MS‐hTau‐induced spatial memory deficits with preservation of MS–hippocampal cholinergic pathway and removal of tau load; and the beneficial effects of donepezil was more prominent at low dose. Proteomics revealed that MS‐hTau accumulation deregulated multiple signaling pathways with numerous differentially expressed proteins (DEPs). Among them, the vacuolar protein sorting‐associated protein 37D (VP37D), an autophagy‐related protein, was significantly reduced in MS hTau mice; the reduction of VP37D was restored by donepezil, and the effect was more significant at low dose than high dose. These novel evidences reveal a causal role ...