Innate immunity protein IFITM3 is involved in Alzheimer’s disease‐associated microglial response

Abstract Background Alzheimer’s disease (AD) is the most common neurodegenerative disorder that has complex neuropathology which includes an accumulation of amyloid beta (Aβ) plaques, hyper‐phosphorylated tau tangles, and neuroinflammation. Amyloid plaques consist Aβ peptides, which are sequentially cleaved by α or β‐secretase and then γ‐secretase (GS) from amyloid precursor protein (APP). Our lab has previously identified interferon response protein IFITM3 as a GS modulatory protein that is upregulated in the human AD brain as well as in the 5xFAD mouse brain. We have shown that IFITM3 regulates GS activity in neurons, and a deficit in IFITM3 results in decreased GS cleavage of APP, leading to reduced amyloid plaque deposition in the 5xFAD mouse. Method We have generated 5xFAD;IFITM3 −/− ;TREM2 −/− mice and have established stem cell‐derived IFITM3‐/‐ microglial cells. We have used a panel of mouse behavioural and immunohistochemical tests and in vitro microglial assays to investigating the function of IFITM3 in the phagocytic clearance of Aβ by microglia, its interplay with TREM2 and downstream signaling in the context of neuroinflammation. Result We have found that IFITM3 is highly expressed and inducible in glial cells, particularly astrocytes and microglia. We have shown that 5xFAD;IFITM3 −/− mice have partially rescued cognition compared to 5xFAD mice, and have an upregulation of several microglial genes. In our in vitro microglial model, we have found that IFITM3 −/− microglia display enhanced uptake of Aβ peptide, enhanced lysosomal degradation, and enhanced TREM2 expression and signalling. Conclusion We have determined a novel role of IFITM3 in microglia using cellular assays and mouse models. We have also found evidence of an interplay of IFITM3 with TREM2.