School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, SAR.
Sci Rep. 2017 Sep 29;7(1):12456. doi: 10.1038/s41598-017-12334-2.
Excessive generation of amyloid-β peptide (Aβ) by aberrant proteolysis of amyloid precursor protein (APP) is a key event in Alzheimer's disease (AD) pathogenesis. FE65 is a brain-enriched phospho-adaptor protein that interacts with APP and has been shown to modulate APP processing. However, the mechanism(s) that FE65 alters APP processing is still not fully understood. In the present study, we demonstrate that FE65 is phosphorylated at threonine 579 (T579) by glycogen synthase kinase 3β (GSK3β). Moreover, FE65 T579 phosphorylation potentiates γ- and β-secretases-mediated APP processing and Aβ liberation. Additionally, the phosphorylation suppresses FE65 PTB2 intermolecular dimerization but enhances FE65/APP complex formation. Hence, our findings reveal a novel mechanism that GSK3β stimulates amyloidogenic processing of APP by phosphorylation of FE65 at T579.
淀粉样蛋白-β肽（Aβ）的过量生成是阿尔茨海默病（AD）发病机制中的关键事件，其由淀粉样前体蛋白（APP）的异常蛋白水解产生。FE65 是一种脑丰富的磷酸衔接蛋白，与 APP 相互作用，并已被证明可调节 APP 的加工。然而，FE65 改变 APP 加工的机制尚不完全清楚。在本研究中，我们证明 FE65 可被糖原合酶激酶 3β（GSK3β）在苏氨酸 579（T579）处磷酸化。此外，FE65 T579 磷酸化增强 γ-和 β-分泌酶介导的 APP 加工和 Aβ 释放。此外，磷酸化抑制 FE65 PTB2 分子间二聚化，但增强 FE65/APP 复合物的形成。因此，我们的研究结果揭示了一种新的机制，即 GSK3β 通过 FE65 的 T579 磷酸化刺激 APP 的淀粉样蛋白形成加工。
