老年癡呆癥（阿爾茨海默癥，Alzheimer’s disease,，簡稱AD）是老年期最常見的神經(jīng)退行性疾病,，是一種慢性精神致殘及致死性疾病，為六大致死因素之一,。全球用于AD治療的醫(yī)療費用超過全球GDP總值的1%,，相當于全球第18大經(jīng)濟實體。AD的主要發(fā)病機理之一是淀粉樣蛋白前體APP經(jīng)β和γ-Secretase先后剪切產(chǎn)生淀粉樣蛋白Aβ,，并導致腦中Aβ40/Aβ42 比例失調，其中Aβ42極易纖維化聚合,，形成具有更強的神經(jīng)毒性的二聚體或寡聚體,，其過量產(chǎn)生并聚集就形成了淀粉樣蛋白（Aβ）沉淀，進一步引發(fā)AD。Aph-1aL是近年來發(fā)現(xiàn)的γ-Secretase酶復合體組成核心成分之一,。
中科院上海生科院生化與細胞所裴鋼研究組的最新研究發(fā)現(xiàn)，β休止蛋白（β-arrestin1）可以通過結合γ-Secretase酶復合體組成核心成分Aph-1羧基末端而與之相互作用,，增強APH1/NCT pre-complex的形成，從而促進了γ-Secretase全酶復合體的裝配及活性,，增加了其剪切APP產(chǎn)生淀粉樣蛋白Aβ40/Aβ42的產(chǎn)生。通過遺傳操作,，敲除掉AD模型小鼠中β-arrestin1基因,，發(fā)現(xiàn)β-arrestin1缺失對AD小鼠的學習記憶,，空間記憶以及物體辨別記憶都有顯著改善,，同時其腦內(nèi)Aβ40/Aβ42和淀粉樣斑塊都得以明顯下調。此外,，利用Aph-1羧基端小肽可以干擾β-arrestin1與APH-aL的相互作用從而實現(xiàn)對γ-Secretase酶復合體APP剪切產(chǎn)生Aβ40/Aβ42過程的抑制作用,，而對γ-Secretase酶復合體的正常生理功能沒有影響,，避免了γ-Secretase抑制劑的一系列副作用。這一工作不僅深入闡述了細胞信號轉導分子β休止蛋白在AD發(fā)病進程中發(fā)揮著重要的調控功能，并且首次闡明了細胞能夠通過不同的調控機制對γ-Secretase活性進行底物特異的活性調控,。這一發(fā)現(xiàn)為更進一步深入揭示阿爾茨海默綜合癥發(fā)病機制,，從而開發(fā)新的治療手段提供全新的思路。
相關研究成果于12月4日在線發(fā)表于國際學術期刊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
