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

• DOI: 10.1038/s41380-018-0286-z
• Publication Date: 2018-10-31T17:08:31Z
• Authors: Zhentao Zhang; Xiao-Guang Li; Zhi-Hao Wang; Mingke Song; Shan Ping Yu; Seong Su Kang; Xia Liu; Zhaohui Zhang; Manling Xie; Gong-Ping Liu; Jian-Zhi Wang; Keqiang Ye
• Keywords: Amyloid beta-Protein Precursor; 0303 health sciences; 03 medical and health sciences; Amyloid beta-Peptides; STAT1 Transcription Factor; Alzheimer Disease; Aspartic Acid Endopeptidases; Humans; Neurofibrillary Tangles; tau Proteins; Amyloid Precursor Protein Secretases

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.