| First Author | Hur JY | Year | 2020 |
| Journal | Nature | Volume | 586 |
| Issue | 7831 | Pages | 735-740 |
| PubMed ID | 32879487 | Mgi Jnum | J:297401 |
| Mgi Id | MGI:6472582 | Doi | 10.1038/s41586-020-2681-2 |
| Citation | Hur JY, et al. (2020) The innate immunity protein IFITM3 modulates gamma-secretase in Alzheimer's disease. Nature 586(7831):735-740 |
| abstractText | Innate immunity is associated with Alzheimer's disease(1), but the influence of immune activation on the production of amyloid-beta is unknown(2,3). Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a gamma-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-beta. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to gamma-secretase and upregulates its activity, thereby increasing the production of amyloid-beta. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces gamma-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 gamma-secretase activity. The amount of IFITM3 in the gamma-secretase complex has a strong and positive correlation with gamma-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which gamma-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased. |
