• Juan Deng, Ahsan Habib, Demian F Obregon, Steven W Barger, Brian Giunta, Yan-Jiang Wang, Huayan Hou, Darrell Sawmiller, and Jun Tan.
• Rashid Laboratory for Developmental Neurobiology, Department of Psychiatry & Behavioral Neurosciences, Morsani College of Medicine, Silver Child Development Center, University of South Florida, Tampa, Florida, USA.
• J. Neurochem. 2015 Nov 1; 135 (3): 630-7.

AbstractWe 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.© 2015 International Society for Neurochemistry.

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