The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.
The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.
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DOI：
10.1038/s41586-020-2681-2
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Li YM
中科院分区：
文献类型：
--
作者：
Hur JY;Frost GR;Wu X;Crump C;Pan SJ;Wong E;Barros M;Li T;Nie P;Zhai Y;Wang JC;Tcw J;Guo L;McKenzie A;Ming C;Zhou X;Wang M;Sagi Y;Renton AE;Esposito BT;Kim Y;Sadleir KR;Trinh I;Rissman RA;Vassar R;Zhang B;Johnson DS;Masliah E;Greengard P;Goate A;Li YM
先天免疫与阿尔茨海默病（Alzheimer disease，AD）有关，但免疫激活对Aβ产生的影响尚不清楚。在这里，我们确定干扰素诱导的跨膜蛋白3（IFITM 3）作为γ-分泌酶调节蛋白，建立炎症影响Aβ生成的机制。神经元和星形胶质细胞中的炎性细胞因子诱导IFITM 3，IFITM 3与γ-分泌酶结合并上调其Aβ产生活性。在小鼠模型中，IFITM 3表达随着衰老和家族性阿尔茨海默病基因的增加而增加。此外，IFITM 3敲除降低了5XFAD小鼠中γ-分泌酶活性和淀粉样蛋白斑块的形成。IFITM 3蛋白在表现出较高γ-分泌酶活性的迟发性AD（LOAD）患者亚组中上调。γ-分泌酶复合物中IFITM 3的量与LOAD中γ-分泌酶活性具有强的正相关性。这些发现揭示了一种前所未有的机制，其中γ-分泌酶通过神经炎症被IFITM 3调节并增加AD的风险。
Innate immunity is associated with Alzheimer disease (AD), however, the influence of immune activation on Aβ production is unknown. Here, we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, establishing a mechanism by which inflammation impacts Aβ generation. Inflammatory cytokines in neurons and astrocytes induce IFITM3 which binds to γ-secretase and upregulates its activity for Aβ production. IFITM3 expression is increased with aging and familial Alzheimer disease’s genes in mouse models. Furthermore, IFITM3 knock out reduces γ-secretase activity and the formation of amyloid plaques in 5XFAD mice. IFITM3 protein is upregulated in a subset of late onset AD (LOAD) patients that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in LOAD. These findings reveal an unprecedented mechanism in which γ-secretase is modulated by IFITM3 by neuroinflammation and increases risks for AD.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
9.8
作者：
Allen, Mariet;Carrasquillo, Minerva M.;Funk, Cory;Heavner, Benjamin D.;Zou, Fanggeng;Younkin, Curtis S.;Burgess, Jeremy D.;Chai, High-Seng;Crook, Julia;Eddy, James A.;Li, Hongdong;Logsdon, Ben;Peters, Mette A.;Dang, Kristen K.;Wang, Xue;Serie, Daniel;Wang, Chen;Thuy Nguyen;Lincoln, Sarah;Malphrus, Kimberly;Bisceglio, Gina;Li, Ma;Golde, Todd E.;Mangravite, Lara M.;Asmann, Yan;Price, Nathan D.;Petersen, Ronald C.;Graff-Radford, Neill R.;Dickson, Dennis W.;Younkin, Steven G.;Ertekin-Taner, Nilufer
通讯作者：
Ertekin-Taner, Nilufer
影响因子：
4
作者：
Gertsik, Natalya;Chau, De-Ming;Li, Yue-Ming
通讯作者：
Li, Yue-Ming
影响因子：
15
作者：
Imamura, Yuki;Watanabe, Naoto;Higuchi, Tsunehiko
通讯作者：
Higuchi, Tsunehiko
影响因子：
4.8
作者：
Gertsik N;Chiu D;Li YM
通讯作者：
Li YM