Interferon-induced transmembrane protein 3 (IFITM3) as a neuroimmune regulator in Alzheimer’s disease: emerging roles in astrocyte activation and pathological signaling

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, Tau pathology, and persistent neuroinflammation. Although therapeutic strategies targeting Aβ and Tau have significantly advanced our understanding of AD pathogenesis, growing attention has been directed toward the role of immune dysregulation in AD progression, highlighting the need to identify immune regulators that contribute to AD-associated pathological mechanisms. Interferon-induced transmembrane protein 3 (IFITM3), an interferon-responsive membrane protein involved in innate immune responses, has recently emerged as a potential regulator of AD-associated pathological processes. Experimental and transcriptomic studies suggest that IFITM3 modulates γ-secretase activity, amyloidogenic processing, inflammatory activation, and membrane trafficking pathways. Notably, IFITM3 is enriched in reactive astrocyte populations, raising the possibility that astrocytic IFITM3 contributes to the regulation of interferon-associated glial responses and neuroinflammatory signaling. In this review, we summarize current evidence regarding the role of IFITM3 in AD, focusing on astrocyte-associated mechanisms, including inflammatory regulation, endo-lysosomal dysfunction, and extracellular vesicle-mediated communication. We further discuss IFITM3-related signaling across astrocytes, neurons, microglia, vascular cells, and peripheral immune compartments, as well as emerging therapeutic approaches targeting IFITM3-associated pathways. Collectively, current evidence suggests that IFITM3 may serve as a potential regulatory interface connecting interferon activation, neuroimmune dysregulation, amyloid metabolism, and neuroinflammatory signaling, providing new perspectives on astrocyte-mediated mechanisms and therapeutic intervention in AD.