Details

Autor(en) / Beteiligte

• Deng, Juan
• Habib, Ahsan
• Obregon, Demian F
• Barger, Steven W
• Giunta, Brian
• Wang, Yan-Jiang
• Hou, Huayan
• Sawmiller, Darrell
• Tan, Jun

Titel

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

Ist Teil von

• Journal of neurochemistry, 2015-11, Vol.135 (3), p.630

Ort / Verlag

New York: Blackwell Publishing Ltd

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• We recently found that sAPP[alpha] decreases amyloid-beta generation by directly associating with [beta]-site amyloid precursor protein (APP)-converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases glycogen synthase kinase 3 beta (GSK3[beta])-mediated Alzheimer's disease (AD)-like tau phosphorylation in AD patient-derived neurons, we determined whether sAPP[alpha] also reduces GSK3[beta]-mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK3[beta] (Ser9) in primary neurons from sAPP[alpha] over-expressing mice. Further, recombinant human sAPP[alpha] evoked the same phenomenon in SH-SY5Y cells. Further, in SH-SY5Y cells over-expressing BACE1, and HeLa cells over-expressing human tau, sAPP[alpha] reduced GSK3[beta] activity and tau phosphorylation. Importantly, the reductions in GSK3[beta] activity and tau phosphorylation elicited by sAPP[alpha] were prevented by BACE1 but not [gamma]-secretase inhibition. In accord, AD mice over-expressing human sAPP[alpha] had less GSK3[beta] activity and tau phosphorylation compared with controls. These results implicate a direct relationship between APP [beta]-processing and GSK3[beta]-mediated tau phosphorylation and further define the central role of sAPP[alpha] in APP autoregulation and AD pathogenesis. Hypothesized pathway for sAPP[alpha]-mediated reduction of tau phosphorylation: Soluble amyloid precursor protein alpha (sAPP[alpha]) increases glycogen synthase kinase 3 beta (GSK3[beta]) inhibitory phosphorylation by inhibiting [beta]-site APP-converting enzyme 1 (BACE1) and followed by reduction of tau phosphorylation. BACE1 inhibition also results in a decrease of amyloid-beta (A[beta]) production. We believe these findings might provide a new strategy to use sAPP[alpha], in treating both A[beta] and tau pathology.