eNAMPT-IFITM3 axis links neuroinflammation to γ-secretase activation

Amyloid-β (Aβ) accumulation and neuroinflammation are central features of Alzheimer's disease (AD), yet the molecular link connecting inflammatory signaling to γ-secretase activation remains poorly understood. Here, using a cell-based gain-of-function screen with a cDNA library, we identify nicotinamide phosphoribosyltransferase (NAMPT) as a positive regulator of γ-secretase activity. We demonstrate that extracellular NAMPT (eNAMPT) acts as a paracrine factor binding to cell-surface interferon-induced transmembrane protein 3 (IFITM3), enhancing its protein stability and promoting γ-secretase complex assembly to heighten amyloidogenic processing, independently of its NAD+ biosynthetic function. Pathologically, NAMPT levels are elevated in patients with AD and mouse models. Furthermore, systemic inflammation induced by lipopolysaccharide (LPS) enhances NAMPT expression and promotes the NAMPT-IFITM3 interaction and γ-secretase complex assembly in vivo, whereas NAMPT neutralization with an antibody suppresses LPS-induced γ-secretase activation. These findings establish the eNAMPT-IFITM3 axis as a key molecular link bridging neuroinflammation and γ-secretase-mediated AD pathology.