Unveiling the role of KLF9‐mediated IFITM3 regulation in amyloidogenesis

Abstract Interferon‐induced transmembrane protein 3 (IFITM3) is implicated in the pathogenesis of Alzheimer's Disease (AD) by regulating γ‐secretase activity and subsequent amyloid β (Aβ) generation. However, the regulation of IFITM3 gene expression and the underlying mechanisms remain exclusive. In this study, we aimed to investigate the regulation of the IFITM3 and its role in amyloidogenesis. The functional active promoter of the IFITM3 gene was identified within the 1047 bp of 5′‐flanking regions by luciferase assays. Through chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA), we successfully identified a specific Krüppel‐like factor 9 (KLF9) binding site within the promoter region. Moreover, KLF9 overexpression significantly upregulates IFITM3 expression in vitro and in vivo, which promotes Aβ generation in the hippocampus of mice. Consistently, reduced IFITM3 expression results in a notable decrease of Aβ production. Together, we demonstrate that KLF9 plays a critical role in regulating IFITM3 expression and subsequent Aβ production. It highly suggests that inhibiting KLF9‐mediated IFITM3 expression may have therapeutic potential for AD by reducing Aβ production.