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?-Secretase-cleaved Tau stimulates A? production via upregulating STAT1-BACE1 signaling in Alzheimer's disease.


ABSTRACT: ?-Secretase, an age-dependent asparagine protease, cleaves both amyloid precursor protein (APP) and Tau and is required for amyloid plaque and neurofibrillary tangle pathologies in Alzheimer's disease (AD). However, whether ?-secretase activation is sufficient to trigger AD pathogenesis remains unknown. Here we show that the fragments of ?-secretase-cleavage, APP (586-695) and Tau(1-368), additively drive AD pathogenesis and cognitive dysfunctions. Tau(1-368) strongly augments BACE1 expression and A? generation in the presence of APP. The Tau(1-368) fragment is more robust than full-length Tau in binding active STAT1, a BACE1 transcription factor, and promotes its nuclear translocation, upregulating BACE1 and A? production. Notably, A?-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1-368). Inhibition of these kinases diminishes stimulatory effect of Tau(1-368). Knockout of STAT1 abolishes AD pathologies induced by ?-secretase-generated APP and Tau fragments. Thus, we show that Tau may not only be a downstream effector of A? in the amyloid hypothesis, but also act as a driving force for A?, when cleaved by ?-secretase.

SUBMITTER: Zhang Z 

PROVIDER: S-EPMC6684859 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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δ-Secretase-cleaved Tau stimulates Aβ production via upregulating STAT1-BACE1 signaling in Alzheimer's disease.

Zhang Zhentao Z   Li Xiao-Guang XG   Wang Zhi-Hao ZH   Song Mingke M   Yu Shan Ping SP   Kang Seong Su SS   Liu Xia X   Zhang Zhaohui Z   Xie Manling M   Liu Gong-Ping GP   Wang Jian-Zhi JZ   Ye Keqiang K  

Molecular psychiatry 20181031 2


δ-Secretase, an age-dependent asparagine protease, cleaves both amyloid precursor protein (APP) and Tau and is required for amyloid plaque and neurofibrillary tangle pathologies in Alzheimer's disease (AD). However, whether δ-secretase activation is sufficient to trigger AD pathogenesis remains unknown. Here we show that the fragments of δ-secretase-cleavage, APP (586-695) and Tau(1-368), additively drive AD pathogenesis and cognitive dysfunctions. Tau(1-368) strongly augments BACE1 expression a  ...[more]

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