Medial septum tau accumulation induces spatial memory deficit via disrupting medial septum-hippocampus cholinergic pathway
Authors
Wu, DongqinGao, Di
Yu, Haitao
Pi, Guilin
Xiong, Rui
Lei, Huiyang
Wang, Xin
Liu, Enjie
Ye, Jinwang
Gao, Yang
He, Ting
Jiang, Tao
Sun, Fei
Su, Jingfen
Song, Guoda
Peng, Wenju
Yang, Ying
Wang, Jian-Zhi
Issue Date
2021-05-28Subjects
cholinergic neurondonepezil
medial septum
Tau accumulation
Subject Categories::C730 Metabolic Biochemistry
Metadata
Show full item recordAbstract
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 (MShTau ) 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 MShTau 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 MShTau 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 of tau accumulation in linking MS cholinergic lesion to hippocampus-dependent spatial cognitive damages as seen in the AD patients, and the new tau-removal and autophagy-promoting effects of donepezil may extend its application beyond simple symptom amelioration to potential disease modification.Citation
Wu D, Gao D, Yu H, Pi G, Xiong R, Lei H, Wang X, Liu E, Ye J, Yu H, Gao Y, He T, Jiang T, Sun F, Su J, Song G, Peng W, Yang Y, Wang J-Z (2021) 'Medial septum tau accumulation induces spatial memory deficit via disrupting medial septum-hippocampus cholinergic pathway', Clinical and translational medicine, 11 (6), e428.Publisher
WileyDOI
10.1002/ctm2.428PubMed ID
34185417PubMed Central ID
PMC8161512Additional Links
https://onlinelibrary.wiley.com/doi/10.1002/ctm2.428Type
ArticleLanguage
enISSN
2001-1326ae974a485f413a2113503eed53cd6c53
10.1002/ctm2.428
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