Autor: |
Hur, Ji-Yeun, Frost, Georgia R., Wu, Xianzhong, Crump, Christina, Pan, Si Jia, Wong, Eitan, Barros, Marilia, Li, Thomas, Nie, Pengju, Zhai, Yujia, Wang, Jen Chyong, TCW, Julia, Guo, Lei, McKenzie, Andrew, Ming, Chen, Zhou, Xianxiao, Wang, Minghui, Sagi, Yotam, Renton, Alan E., Esposito, Bianca T. |
Zdroj: |
Nature; 10/29/2020, Vol. 586 Issue 7831, p735-740, 6p |
Abstrakt: |
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. The IFITM3 innate immunity protein directly binds presenilin near the active site and upregulates γ-secretase activity and the production of amyloid-β, and IFITM3 is upregulated in patients with late-onset Alzheimer's disease. [ABSTRACT FROM AUTHOR] |
Databáze: |
Complementary Index |
Externí odkaz: |
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