The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease

被引：250

作者：

Hur, Ji-Yeun ^{[1
]}

Frost, Georgia R. ^{[1
,2
]}

Wu, Xianzhong ^{[1
]}

Crump, Christina ^{[1
,3
]}

Pan, Si Jia ^{[1
]}

Wong, Eitan ^{[1
]}

Barros, Marilia ^{[1
]}

Li, Thomas ^{[1
,2
]}

Nie, Pengju ^{[1
,3
]}

Zhai, Yujia ^{[1
]}

Wang, Jen Chyong ^{[4
]}

TCW, Julia ^{[4
]}

Guo, Lei ^{[5
]}

McKenzie, Andrew ^{[5
]}

Ming, Chen ^{[5
]}

Zhou, Xianxiao ^{[5
]}

Wang, Minghui ^{[5
]}

Sagi, Yotam ^{[6
]}

Renton, Alan E. ^{[4
]}

Esposito, Bianca T. ^{[4
]}

Kim, Yong ^{[6
]}

Sadleir, Katherine R. ^{[7
]}

Trinh, Ivy ^{[8
]}

Rissman, Robert A. ^{[8
]}

Vassar, Robert ^{[7
]}

Zhang, Bin ^{[5
]}

Johnson, Douglas S. ^{[9
]}

Masliah, Eliezer ^{[8
]}

Greengard, Paul ^{[6
]}

Goate, Alison ^{[4
,5
]}

Li, Yue-Ming ^{[1
,2
,3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Chem Biol Program, 1275 York Ave, New York, NY 10021 USA

[2] Cornell Univ, Program Neurosci, Weill Grad Sch Med Sci, New York, NY USA

[3] Cornell Univ, Weill Grad Sch Med Sci, Program Pharmacol, New York, NY 10021 USA

[4] Icahn Sch Med Mt Sinai, Dept Neurosci, Ronald M Loeb Ctr Alzheimers Dis, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Mt Sinai Ctr Transformat Dis Modeling, Dept Genet & Genom Sci, New York, NY 10029 USA

[6] Rockefeller Univ, Lab Mol & Cellular Neurosci, New York, NY USA

[7] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA

[8] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[9] Pfizer Worldwide Res & Dev, Cambridge, MA USA

来源：

NATURE | 2020年 / 586卷 / 7831期

基金：

美国国家卫生研究院;

关键词：

DETERGENT-RESISTANT MEMBRANES; INHIBITORS; RISK; PRESENILIN-1; ASSOCIATION; ACTIVATION; MUTATIONS; REVEALS; NEURONS; BINDING;

D O I：

10.1038/s41586-020-2681-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The IFITM3 innate immunity protein directly binds presenilin near the active site and upregulates gamma-secretase activity and the production of amyloid-beta, and IFITM3 is upregulated in patients with late-onset Alzheimer's disease. Innate immunity is associated with Alzheimer's disease(1), but the influence of immune activation on the production of amyloid-beta is unknown(2,3). Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a gamma-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-beta. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to gamma-secretase and upregulates its activity, thereby increasing the production of amyloid-beta. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces gamma-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher gamma-secretase activity. The amount of IFITM3 in the gamma-secretase complex has a strong and positive correlation with gamma-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which gamma-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.

引用

页码：735 / +

页数：16

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