Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3 signaling pathway

We recently found that sAPP decreases amyloid-beta generation by directly associating with -site amyloid precursor protein (APP)-converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases glycogen synthase kinase 3 beta (GSK3)-mediated Alzheimer's disease (AD)-like tau phosphorylation in AD patient-derived neurons, we determined whether sAPP also reduces GSK3-mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK3 (Ser9) in primary neurons from sAPP over-expressing mice. Further, recombinant human sAPP evoked the same phenomenon in SH-SY5Y cells. Further, in SH-SY5Y cells over-expressing BACE1, and HeLa cells over-expressing human tau, sAPP reduced GSK3 activity and tau phosphorylation. Importantly, the reductions in GSK3 activity and tau phosphorylation elicited by sAPP were prevented by BACE1 but not -secretase inhibition. In accord, AD mice over-expressing human sAPP had less GSK3 activity and tau phosphorylation compared with controls. These results implicate a direct relationship between APP -processing and GSK3-mediated tau phosphorylation and further define the central role of sAPP in APP autoregulation and AD pathogenesis.