Scheinfeld Meir H, Ghersi Enrico, Davies Peter, D'Adamio Luciano
Department of Microbiology & Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
J Biol Chem. 2003 Oct 24;278(43):42058-63. doi: 10.1074/jbc.M304853200. Epub 2003 Aug 13.
Alzheimer's disease (AD) is genetically linked to the processing of amyloid beta protein precursor (AbetaPP). Aside from being the precursor of the amyloid beta (Abeta) found in plaques in the brains of patients with AD, little is known regarding the functional role of AbetaPP. We have recently reported biochemical evidence linking AbetaPP to the JNK signaling cascade by finding that JNK-interacting protein-1 (JIP-1) binds AbetaPP. In order to study the functional implications of this interaction we assayed the carboxyl-terminal of AbetaPP for phosphorylation. We found that the threonine 668 within the AbetaPP intracellular domain (AID or elsewhere AICD) is indeed phosphorylated by JNK1. We surprisingly found that although JIP-1 can facilitate this phosphorylation, it is not required for this process. We also found that JIP-1 only facilitated phosphorylation of AbetaPP but not of the two other family members APLP1 (amyloid precursor-like protein 1) and APLP2. Understanding the connection between AbetaPP phosphorylation and the JNK signaling pathway, which mediates cell response to stress may have important implications in understanding the pathogenesis of Alzheimer's disease.
阿尔茨海默病（AD）在基因上与淀粉样β蛋白前体（AβPP）的加工过程相关。除了作为在AD患者大脑斑块中发现的淀粉样β（Aβ）的前体之外，人们对AβPP的功能作用知之甚少。我们最近报道了通过发现JNK相互作用蛋白-1（JIP-1）与AβPP结合，将AβPP与JNK信号级联联系起来的生化证据。为了研究这种相互作用的功能意义，我们检测了AβPP羧基末端的磷酸化情况。我们发现AβPP细胞内结构域（AID或其他地方称为AICD）内的苏氨酸668确实被JNK1磷酸化。我们令人惊讶地发现，尽管JIP-1可以促进这种磷酸化，但该过程并不需要它。我们还发现JIP-1仅促进AβPP的磷酸化，而不促进另外两个家族成员APLP1（淀粉样前体样蛋白1）和APLP2的磷酸化。理解AβPP磷酸化与介导细胞对应激反应的JNK信号通路之间的联系，可能对理解阿尔茨海默病的发病机制具有重要意义。
