Work

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

Year: 2015

Type: article

Abstract: We recently found that sAPPα decreases amyloid‐beta generation by directly associating with β‐site amyloid precursor protein (APP)‐converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases glycogen synthase kinase 3 beta (GSK3β)‐mediated Alzheimer's disease (AD)‐like tau phosphorylation in AD patient‐derived neurons, we determined whether sAPPα also reduces GSK3β‐mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK3β (Ser9) in primary neurons from sAPPα over‐expressing mice. Further, recombinant human sAPPα evoked the same phenomenon in SH‐SY5Y cells. Further, in SH‐SY5Y cells over‐expressing BACE1, and HeLa cells over‐expressing human tau, sAPPα reduced GSK3β activity and tau phosphorylation. Importantly, the reductions in GSK3β activity and tau phosphorylation elicited by sAPPα were prevented by BACE1 but not γ‐secretase inhibition. In accord, AD mice over‐expressing human sAPPα had less GSK3β activity and tau phosphorylation compared with controls. These results implicate a direct relationship between APP β‐processing and GSK3β‐mediated tau phosphorylation and further define the central role of sAPPα in APP autoregulation and AD pathogenesis. image 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.

Source: Journal of Neurochemistry

DOI: 10.1111/jnc.13351