@article{f4f33dd1c4df48d89d48fef76c1eb3f2,
title = "The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer{\textquoteright}s disease",
abstract = "Innate immunity is associated with Alzheimer{\textquoteright}s disease1, but the influence of immune activation on the production of amyloid-β is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-β. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-β. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer{\textquoteright}s disease genes. Furthermore, knockout of IFITM3 reduces γ-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{\textquoteright}s disease 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 samples from patients with late-onset Alzheimer{\textquoteright}s disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer{\textquoteright}s disease is thereby increased.",
author = "Hur, {Ji Yeun} and Frost, {Georgia R.} and Xianzhong Wu and Christina Crump and Pan, {Si Jia} and Eitan Wong and Marilia Barros and Thomas Li and Pengju Nie and Yujia Zhai and Wang, {Jen Chyong} and Julia Tcw and Lei Guo and Andrew McKenzie and Chen Ming and Xianxiao Zhou and Minghui Wang and Yotam Sagi and Renton, {Alan E.} and Esposito, {Bianca T.} and Yong Kim and Sadleir, {Katherine R.} and Ivy Trinh and Rissman, {Robert A.} and Robert Vassar and Bin Zhang and Johnson, {Douglas S.} and Eliezer Masliah and Paul Greengard and Alison Goate and Li, {Yue Ming}",
note = "Funding Information: Acknowledgements We thank A. Kentsis and R. Hendrickson for LC–MS/MS and proteomic analysis. We thank H. Brogdon and N. L. Nadon for mouse brains. We thank E. Sikora for Apoe genotyping, D. Yarilin for immunostaining, S. Fujisawa and Y. Romin for help with microscopy, and S. Shuldberg for human brain samples. We thank S. Wagner for providing NGP-97555. This work is supported by the JPB Foundation (Y.-M.L., P.G. and A.G.), the Fisher Center for Alzheimer{\textquoteright}s Research Foundation (P.G.), Cure Alzheimer{\textquoteright}s Fund (Y.-M.L), the National Institutes of Health R01NS096275 (Y.-M.L.), RF1AG057593 (Y.-M.L.), R01AG061350 (Y.-M.L.), R01AG046170 (B.Z.), RF1AG057440 (B.Z.) and R01AG057907 (B.Z.). We also acknowledge the MSK Cancer Center Support Grant/Core Grant (grant P30 CA008748) the ADRC parent grant (P30 AG062429), Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of MSKCC, and the William Randolph Hearst Fund in Experimental Therapeutics. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = oct,
day = "29",
doi = "10.1038/s41586-020-2681-2",
language = "English",
volume = "586",
pages = "735--740",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7831",
}