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. Esposito, Yong Kim, Katherine R. Sadleir, Ivy Trinh, Robert A. Rissman, Robert Vassar, Bin Zhang, Douglas S. Johnson, Eliezer Masliah, Paul Greengard, Alison Goate and Yue-Ming Li ()
Additional contact information
Ji-Yeun Hur: Memorial Sloan Kettering Cancer Center
Georgia R. Frost: Memorial Sloan Kettering Cancer Center
Xianzhong Wu: Memorial Sloan Kettering Cancer Center
Christina Crump: Memorial Sloan Kettering Cancer Center
Si Jia Pan: Memorial Sloan Kettering Cancer Center
Eitan Wong: Memorial Sloan Kettering Cancer Center
Marilia Barros: Memorial Sloan Kettering Cancer Center
Thomas Li: Memorial Sloan Kettering Cancer Center
Pengju Nie: Memorial Sloan Kettering Cancer Center
Yujia Zhai: Memorial Sloan Kettering Cancer Center
Jen Chyong Wang: Icahn School of Medicine at Mount Sinai
Julia Tcw: Icahn School of Medicine at Mount Sinai
Lei Guo: Icahn School of Medicine at Mount Sinai
Andrew McKenzie: Icahn School of Medicine at Mount Sinai
Chen Ming: Icahn School of Medicine at Mount Sinai
Xianxiao Zhou: Icahn School of Medicine at Mount Sinai
Minghui Wang: Icahn School of Medicine at Mount Sinai
Yotam Sagi: Rockefeller University
Alan E. Renton: Icahn School of Medicine at Mount Sinai
Bianca T. Esposito: Icahn School of Medicine at Mount Sinai
Yong Kim: Rockefeller University
Katherine R. Sadleir: Northwestern University
Ivy Trinh: University of California San Diego
Robert A. Rissman: University of California San Diego
Robert Vassar: Northwestern University
Bin Zhang: Icahn School of Medicine at Mount Sinai
Douglas S. Johnson: Pfizer Worldwide Research and Development
Eliezer Masliah: University of California San Diego
Paul Greengard: Rockefeller University
Alison Goate: Icahn School of Medicine at Mount Sinai
Yue-Ming Li: Memorial Sloan Kettering Cancer Center

Nature, 2020, vol. 586, issue 7831, 735-740

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2681-2

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