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

delta-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 delta-secretase activation is sufficient to trigger AD pathogenesis remains unknown. Here we show that the fragments of delta-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 beta 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 beta production. Notably, A beta-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 delta-secretase-generated APP and Tau fragments. Thus, we show that Tau may not only be a downstream effector of A beta in the amyloid hypothesis, but also act as a driving force for A beta, when cleaved by delta-secretase.

Automated summary

This study reveals that the fragments generated by delta-secretase cleavage, APP and Tau, act additively to drive AD pathogenesis and cognitive dysfunctions. Tau(1-368) fragment enhances BACE1 expression and A beta generation, and has a more robust effect than full-length Tau, promoting the nuclear translocation of active STAT1 and increasing BACE1 and A beta production. Further mechanism involving A beta-activated kinases phosphorylating STAT1 and its association with Tau(1-368) is also discussed.