CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France.
ACS Chem Neurosci. 2013 Jan 16;4(1):130-40. doi: 10.1021/cn300095t. Epub 2012 Oct 13.
In addition to the amyloidogenic pathway, amyloid precursor protein (APP) can be cleaved by α-secretases, producing soluble and neuroprotective APP alpha (sAPPα) (nonamyloidogenic pathway) and thus preventing the generation of pathogenic amyloid-β. However, the mechanisms regulating APP cleavage by α-secretases remain poorly understood. Here, we showed that expression of serotonin type 4 receptors (5-HT(4)Rs) constitutively (without agonist stimulation) induced APP cleavage by the α-secretase ADAM10 and the release of neuroprotective sAPPα in HEK-293 cells and cortical neurons. This effect was independent of cAMP production. Interestingly, we demonstrated that 5-HT(4) receptors physically interacted with the mature form of ADAM10. Stimulation of 5-HT(4) receptors by an agonist further increased sAPPα secretion, and this effect was mediated by cAMP/Epac signaling. These findings describe a new mechanism whereby a GPCR constitutively stimulates the cleavage of APP by α-secretase and promotes the nonamyloidogenic pathway of APP processing.
除淀粉样蛋白生成途径外，淀粉样前体蛋白（APP）还可被α-分泌酶切割，产生可溶性且具有神经保护作用的 APP α（sAPPα）（非淀粉样蛋白生成途径），从而防止致病性淀粉样β的产生。然而，调节α-分泌酶切割 APP 的机制仍知之甚少。本研究表明，5-羟色胺 4 型受体（5-HT4Rs）的表达可在不依赖激动剂刺激的情况下，持续诱导 HEK-293 细胞和皮质神经元中 ADAM10 介导的 APP 切割和具有神经保护作用的 sAPPα 的释放。这种效应与 cAMP 的产生无关。有趣的是，我们证明 5-HT4R 与 ADAM10 的成熟形式存在物理相互作用。激动剂刺激 5-HT4R 可进一步增加 sAPPα 的分泌，而这种作用是由 cAMP/Epac 信号介导的。这些发现描述了一种新的机制，即 GPCR 持续刺激 APP 通过 α-分泌酶的切割，并促进 APP 加工的非淀粉样蛋白生成途径。
