한빛사 논문
Ji-Yeun Hur1,10, Georgia R. Frost1,2,10, Xianzhong Wu1, Christina Crump1,3, Si Jia Pan1, Eitan Wong1, Marilia Barros1, Thomas Li1,2, Pengju Nie1,3, Yujia Zhai1, Jen Chyong Wang4, Julia TCW4, Lei Guo5, Andrew McKenzie5, Chen Ming5, Xianxiao Zhou5, Minghui Wang5, Yotam Sagi6, Alan E. Renton4, Bianca T. Esposito4, Yong Kim6, Katherine R. Sadleir7, Ivy Trinh8, Robert A. Rissman8, Robert Vassar7, Bin Zhang5, Douglas S. Johnson9, Eliezer Masliah8, Paul Greengard6,11, Alison Goate4,5 & Yue-Ming Li1,2,3,*
1Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2Program of Neurosciences, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA. 3Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA. 4Ronald M. Loeb Center for Alzheimer’s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 5Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 6Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY, USA. 7Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. 8Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. 9Pfizer Worldwide Research and Development, Cambridge, MA, USA. 10These authors contributed equally: Ji-Yeun Hur, Georgia R. Frost. 11Deceased: Paul Greengard.
*Corresponding author
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.
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