δ-Secretase-cleaved Tau stimulates Aß production via upregulating STAT1-BACE1 signaling in Alzheimer's disease.
Mol Psychiatry
; 26(2): 586-603, 2021 02.
Article
in En
| MEDLINE
| ID: mdl-30382187
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 Aß 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 Aß production. Notably, Aß-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 Aß in the amyloid hypothesis, but also act as a driving force for Aß, when cleaved by δ-secretase.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Amyloid Precursor Protein Secretases
/
Alzheimer Disease
Limits:
Humans
Language:
En
Journal:
Mol Psychiatry
Journal subject:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Year:
2021
Type:
Article
Affiliation country:
United States