Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK 3β signaling pathway

Abstract We recently found that s APP α decreases amyloid‐beta generation by directly associating with β‐site amyloid precursor protein ( APP )‐converting enzyme 1 ( BACE 1), thereby modulating APP processing. Because inhibition of BACE 1 decreases glycogen synthase kinase 3 beta ( GSK 3β)‐mediated Alzheimer's disease ( AD )‐like tau phosphorylation in AD patient‐derived neurons, we determined whether s APP α also reduces GSK 3β‐mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK 3β (Ser9) in primary neurons from s APP α over‐expressing mice. Further, recombinant human s APP α evoked the same phenomenon in SH ‐ SY 5Y cells. Further, in SH ‐ SY 5Y cells over‐expressing BACE 1, and HeLa cells over‐expressing human tau, s APP α reduced GSK 3β activity and tau phosphorylation. Importantly, the reductions in GSK 3β activity and tau phosphorylation elicited by s APP α were prevented by BACE 1 but not γ‐secretase inhibition. In accord, AD mice over‐expressing human s APP α had less GSK 3β activity and tau phosphorylation compared with controls. These results implicate a direct relationship between APP β‐processing and GSK 3β‐mediated tau phosphorylation and further define the central role of s APP α in APP autoregulation and AD pathogenesis.Hypothesized pathway for sAPPα‐mediated reduction of tau phosphorylation: Soluble amyloid precursor protein alpha (sAPPα) increases glycogen synthase kinase 3 beta (GSK3β) inhibitory phosphorylation by inhibiting β‐site APP‐converting enzyme 1 (BACE1) and followed by reduction of tau phosphorylation. BACE1 inhibition also results in a decrease of amyloid‐beta (Aβ) production. We believe these findings might provide a new strategy to use sAPPα, in treating both Aβ and tau pathology.