The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease Journal Article
| Authors: | Hur, J. Y.; Frost, G. R.; Wu, X.; Crump, C.; Pan, S. J.; Wong, E.; Barros, M.; Li, T.; Nie, P.; Zhai, Y.; Wang, J. C.; TCW, J.; Guo, L.; McKenzie, A.; Ming, C.; Zhou, X.; Wang, M.; Sagi, Y.; Renton, A. E.; Esposito, B. T.; Kim, Y.; Sadleir, K. R.; Trinh, I.; Rissman, R. A.; Vassar, R.; Zhang, B.; Johnson, D. S.; Masliah, E.; Greengard, P.; Goate, A.; Li, Y. M. |
| Article Title: | The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease |
| 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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | adult; clinical article; controlled study; human tissue; protein expression; aged; unclassified drug; human cell; disease course; pathogenesis; nonhuman; protein analysis; animal cell; mouse; animal tissue; gene expression; embryo; astrocyte; inflammation; protein; enzyme activity; risk factor; mus musculus; innate immunity; aging; upregulation; immunity; cell interaction; nerve cell; alzheimer disease; gamma secretase; enzyme; amyloid beta protein; antimicrobial activity; nervous system inflammation; nervous system disorder; very elderly; cell component; human; male; female; priority journal; article; protein ifitm3 |
| Journal Title: | Nature |
| Volume: | 586 |
| Issue: | 7831 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-10-29 |
| Start Page: | 735 |
| End Page: | 740 |
| Language: | English |
| DOI: | 10.1038/s41586-020-2681-2 |
| PUBMED: | 32879487 |
| PROVIDER: | scopus |
| PMCID: | PMC7919141 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2020 -- Source: Scopus |
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