Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3β signaling pathway.
Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3β signaling pathway.
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DOI：
10.1111/jnc.13351
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发表时间：
2015-11
影响因子：
4.7
通讯作者：
Tan J
中科院分区：
文献类型：
--
作者：
Deng J;Habib A;Obregon DF;Barger SW;Giunta B;Wang YJ;Hou H;Sawmiller D;Tan J
We recently found that sAPPα decreases Aβ generation by directly associating with β-site amyloid precursor protein (APP) converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases 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 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 overexpressing BACE1, and HeLa cells overexpressing 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 overexpressing 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.
