SCG10通過促進(jìn)淀粉樣前體蛋白APP轉(zhuǎn)運(yùn)到細(xì)胞表面增加其α型加工

滕俊琳 王晶晶

摘 要：淀粉樣前體蛋白（APP）的β切割所產(chǎn)生的Aβ阿爾茨海默病（Alzheimer's disease，AD）致病因子。APP的加工方式與特定的亞細(xì)胞區(qū)域相關(guān)，并受到多個(gè)與轉(zhuǎn)運(yùn)相關(guān)的因子的影響。我們實(shí)驗(yàn)結(jié)果顯示SCG10直接與APP的胞內(nèi)結(jié)構(gòu)域KFFEQ基序相結(jié)合促進(jìn)APP的α型加工過程。敲低SCG10導(dǎo)致α型加工產(chǎn)物sAPPα和CTFα的減少，從而增加了Aβ1-40和Aβ1-42的量。增加SCG10的表達(dá)量，可以促進(jìn)APP從高爾基體運(yùn)往細(xì)胞表面，減少β切割，降低Aβ的量。在APPswe/PS1dE9轉(zhuǎn)基因小鼠海馬中增加SCG10的表達(dá)量能夠減少該部位Aβ積累和淀粉樣斑塊形成。綜上所述，這些結(jié)果表明SCG10在預(yù)防和治療AD中有潛在的作用。

關(guān)鍵詞：淀粉樣前體蛋白 Aβ阿爾茨海默病 sAPPα SCG10

SCG10 Promotes Non-amyloidogenic Processing of Amyloid Precursor Protein by Facilitating Its Trafficking to the Cell Surface

Teng Junlin Wang Jingjing

（Peking University）

Abstract：The processing of amyloid precursor protein （APP） is a key event in the pathogenesis of Alzheimersdisease. Since certain cleavage pathways tend to occur in particular subcellular compartments， the processing of APP is greatly influenced by factors which regulate its trafficking. Here we report that SCG10 directly interacts with the KFFEQ motif of the APP intracellular domain and promotes the non-amyloidogenic processing of APP. Knockdown of SCG10 led to decreases in α cleavage products， sAPPα and CTFα， while increases of both Aβ1-40 and Aβ1-42. Elevation of SCG10 induced APP accumulation in post-Golgi vesicles and on the cell surface by facilitating its secretory pathway. In addition， the APP processing was dependent on the palmitoylation-mediated membrane-anchoring of SCG10. Furthermore， elevation of SCG10 reduced Aβ accumulation and amyloid plaque formation in the hippocampus of APPswe/PS1dE9 mice. Taken together， theseresults show that SCG10 has a potential role in preventing and treating Alzheimers disease.

Key Words：APP； AD； sAPPα； SCG10； Anterograde transport

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