老年痴呆症（阿尔茨海默症，Alzheimer’s disease，简称AD）是老年期最常见的神经退行性疾病，是一种慢性精神致残及致死性疾病，为六大致死因素之一。全球用于AD治疗的医疗费用超过全球GDP总值的1%，相当于全球第18大经济实体。AD的主要发病机理之一是淀粉样蛋白前体APP经β和γ-Secretase先后剪切产生淀粉样蛋白Aβ，并导致脑中Aβ40/Aβ42 比例失调，其中Aβ42极易纤维化聚合，形成具有更强的神经毒性的二聚体或寡聚体，其过量产生并聚集就形成了淀粉样蛋白（Aβ）沉淀，进一步引发AD。Aph-1aL是近年来发现的γ-Secretase酶复合体组成核心成分之一。
中科院上海生科院生化与细胞所裴钢研究组的最新研究发现，β休止蛋白（β-arrestin1）可以通过结合γ-Secretase酶复合体组成核心成分Aph-1羧基末端而与之相互作用，增强APH1/NCT pre-complex的形成，从而促进了γ-Secretase全酶复合体的装配及活性，增加了其剪切APP产生淀粉样蛋白Aβ40/Aβ42的产生。通过遗传操作，敲除掉AD模型小鼠中β-arrestin1基因，发现β-arrestin1缺失对AD小鼠的学习记忆，空间记忆以及物体辨别记忆都有显著改善，同时其脑内Aβ40/Aβ42和淀粉样斑块都得以明显下调。此外，利用Aph-1羧基端小肽可以干扰β-arrestin1与APH-aL的相互作用从而实现对γ-Secretase酶复合体APP剪切产生Aβ40/Aβ42过程的抑制作用，而对γ-Secretase酶复合体的正常生理功能没有影响，避免了γ-Secretase抑制剂的一系列副作用。这一工作不仅深入阐述了细胞信号转导分子β休止蛋白在AD发病进程中发挥着重要的调控功能，并且首次阐明了细胞能够通过不同的调控机制对γ-Secretase活性进行底物特异的活性调控。这一发现为更进一步深入揭示阿尔茨海默综合症发病机制，从而开发新的治疗手段提供全新的思路。
相关研究成果于12月4日在线发表于国际学术期刊Cell Research。（生物谷Bioon.com）
doi: 10.1038/cr.2012.167
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β-Arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology
Liu X, Zhao X, Zeng X, Bossers K, Swaab DF, Zhao J, Pei G.
Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease in which the γ-secretase-mediated amyloid-β (Aβ) pathology plays an important role. We found that a multifunctional protein, β-arrestin1, facilitated the formation of NCT/APH-1 (anterior pharynx-defective phenotype 1) precomplex and mature γ-secretase complex through its functional interaction with APH-1. Deficiency of β-arrestin1 or inhibition of binding of β-arrestin1 with APH-1 by small peptides reduced Aβ production without affecting Notch processing. Genetic ablation of β-arrestin1 diminished Aβ pathology and behavioral deficits in transgenic AD mice. Moreover, in brains of sporadic AD patients and transgenic AD mice, the expression of β-arrestin1 was upregulated and correlated well with neuropathological severity and senile Aβ plaques. Thus, our study identifies a regulatory mechanism underlying both γ-secretase assembly and AD pathogenesis, and indicates that specific reduction of Aβ pathology can be achieved by regulation of the γ-secretase assembly
