Dr. Oliver Medvedik and the Journal Club will be returning on September 30th at 1:00 PM EDT live on our Facebook page. The topic for this month is going to be a new study that implicates an innate immune inflammatory protein in disease progression using mouse models.
Innate immunity is associated with Alzheimer’s disease, but the influence of immune activation on the production of amyloid-β is unknown. 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.
These findings build on the inflammaging hypotheses of aging, which links the chronic inflammation typically observed during aging with a variety of aging processes and age-related diseases.
Hur, J. Y., Frost, G. R., Wu, X., Crump, C., Pan, S. J., Wong, E., … & Wang, J. C. (2020). The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease. Nature, 1-6.