Format

Send to

Choose Destination
Mol Psychiatry. 2018 Oct 31. doi: 10.1038/s41380-018-0286-z. [Epub ahead of print]

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

Author information

1
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
2
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
3
Pathophysiology Department, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
4
Department of Aneasthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
5
Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
6
Pathophysiology Department, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. wangjz@mails.tjmu.edu.cn.
7
Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. wangjz@mails.tjmu.edu.cn.
8
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA. kye@emory.edu.
9
Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China. kye@emory.edu.

Abstract

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 and Aβ 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 Aβ production. Notably, Aβ-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 δ-secretase-generated APP and Tau fragments. Thus, we show that Tau may not only be a downstream effector of Aβ in the amyloid hypothesis, but also act as a driving force for Aβ, when cleaved by δ-secretase.

PMID:
30382187
PMCID:
PMC6684859
[Available on 2020-04-30]
DOI:
10.1038/s41380-018-0286-z

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center