老年痴呆症是最广泛的痴呆性疾病，导致老年痴呆症的一个重要因素是大脑中beta-淀粉样蛋白的过度产生。beta-淀粉样蛋白是由其前体蛋白APP经BACE1和gamma-分泌酶依次裂解后生成。由于APP是产生beta-淀粉样蛋白的前体，因此对于APP的细胞生物学功能的深入理解，必将有助于开发针对beta-淀粉样蛋白生成的治疗药物。但目前关于APP的细胞生物学功能还不清楚，需要进一步的研究。
厦门大学生物医学研究院的许华曦教授和张云武教授开展的研究发现，APP可以调控gamma-分泌酶在细胞内的转运。在APP缺失的情况下，gamma-分泌酶各个组分在细胞膜上的水平显著增加，使得gamma-分泌酶更多地裂解Notch产生NICD。这些结果从细胞分子水平阐明了APP的一项重要生理学功能，即调控蛋白质的细胞内转运。而APP对于gamma-分泌酶在细胞内定位的调控也会影响gamma-分泌酶对于其不同底物裂解的能力。
这一研究成果对开发老年痴呆症治疗性药物具有重要的指导意义。（生物谷Bioon.com）
生物谷推荐原始出处：
J. Biol. Chem, 10.1074/jbc.M808497200
Intracellular trafficking of presenilin 1 is regulated by β-amyloid precursor protein and phospholipase D1
Yun Liu, Yun-wu Zhang, Xin Wang, Han Zhang, Xiaoqing You, Francesca-Fang Liao, and Huaxi Xu
Neurodegenerative Disease Research, Burnham Institute for Medical Research, La Jolla, CA 92037
Excessive accumulation of β-amyloid peptides (Aβ) in the brain is a major cause for the pathogenesis of Alzheimer’s disease (AD). Aβ is derived from β-amyloid precursor protein (APP) through sequential cleavages by β- and γ-secretases, whose enzymatic activities are tightly controlled by subcellular localization. Delineation of how intracellular trafficking of these secretases and APP is regulated is important for understanding AD pathogenesis. Although APP trafficking is regulated by multiple factors including presenilin 1 (PS1), a major component of the -secretase complex, and phospholipase D1 (PLD1), a phospholipid-modifying enzyme, regulation of intracellular trafficking of PS1/γ-secretase and -secretase is less clear. Here we demonstrate that APP can reciprocally regulate PS1 trafficking: APP deficiency results in faster transport of PS1 from the trans-Golgi network (TGN) to the cell surface and increased steady-state levels of PS1 at the cell surface, which can be reversed by restoring APP levels. Restoration of APP in APP-deficient cells also reduces steady-state levels of other -secretase components (nicastrin, APH-1 and PEN-2) and the cleavage of Notch by PS1/γ-secretase that is more highly correlated with cell surface levels of PS1 than with APP overexpression levels, supporting the notion that Notch is mainly cleaved at the cell surface. In contrast, intracellular trafficking of β-secretase (BACE1) is not regulated by APP. Moreover, we find that PLD1 also regulates PS1 trafficking and that PLD1 overexpression promotes cell surface accumulation of PS1 in an APP-independent manner. Our results clearly elucidate a physiological function of APP in regulating protein trafficking and suggest that intracellular trafficking of PS1/γ-secretase is regulated by multiple factors, including APP and PLD1.
