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

Ji Yeun Hur, Georgia R. Frost, Xianzhong Wu, Christina Crump, Si Jia Pan, Eitan Wong, Marilia Barros, Thomas Li, Pengju Nie, Yujia Zhai, Jen Chyong Wang, Julia Tcw, Lei Guo, Andrew McKenzie, Chen Ming, Xianxiao Zhou, Minghui Wang, Yotam Sagi, Alan E. Renton, Bianca T. EspositoYong Kim, Katherine R. Sadleir, Ivy Trinh, Robert A. Rissman, Robert Vassar, Bin Zhang, Douglas S. Johnson, Eliezer Masliah, Paul Greengard, Alison Goate, Yue Ming Li*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Innate immunity is associated with Alzheimer’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’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’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’s disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer’s disease is thereby increased.

Original languageEnglish (US)
Pages (from-to)735-740
Number of pages6
JournalNature
Volume586
Issue number7831
DOIs
StatePublished - Oct 29 2020

ASJC Scopus subject areas

  • General

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