Abstract
Innate immunity is associated with Alzheimer disease (AD)1, however, the influence of immune activation on Aβ production is unknown2,3. Here, we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, establishing a mechanism by which inflammation impacts Aβ generation. Inflammatory cytokines in neurons and astrocytes induce IFITM3 which binds to γ-secretase and upregulates its activity for Aβ production. IFITM3 expression is increased with aging and familial Alzheimer disease’s genes in mouse models. Furthermore, IFITM3 knock out reduces γ-secretase activity and the formation of amyloid plaques in 5XFAD mice. IFITM3 protein is upregulated in a subset of late onset AD (LOAD) patients 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 LOAD. These findings reveal an unprecedented mechanism in which γ-secretase is modulated by IFITM3 by neuroinflammation and increases risks for AD.
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