FYN, SARS-CoV-2, and IFITM3 in the neurobiology of Alzheimer's disease

Abstract

Introduction: (IFITM3) is an innate immune protein that has been identified as a novel γ-secretase (γs) modulator. FYN is a kinase that stabilizes IFITM3 on the membrane, primes APP for amyloidogenic γs processing and mediates tau oligomerization. The purpose of this study is to explore the role of FYN and IFITM3 in AD and COVID-19, expanding on previous research from our group. Methods: A 520 gene signature containing FYN and IFITM3 (termed Ia) was extracted from a previously published meta-analysis of Alzheimer's disease (AD) bulk- and single nuclei sequencing data. Exploratory analyses involved meta-analysis of bulk and single cell RNA data for IFITM3 and FYN differential expression per CNS site and cellular type. Confirmatory analyses, gene set enrichment analysis (GSEA) on Ia was performed to detect overlapping enriched biological networks between COVID-19 with AD. Results: Bulk RNA data analysis revealed that IFITM3 and FYN were overexpressed in two CNS regions in AD vs. Controls: the temporal cortex Wilcoxon p-value=1.3e-6) and the parahippocampal cortex Wilcoxon p-value=0.012). Correspondingly, single cell RNA analysis of IFITM3 and FYN revealed that it was differentially expressed in neurons, glial and endothelial cells donated b AD patients, when compared to controls. Discussion: IFITM3 and FYN were found as interactors within biological networks overlapping between AD and SARS-CoV-2 infection. Within the context of SARS-CoV-2 induced tau aggregation and interactions between tau and Ab1–42, the FYN – IFITM3 regulome may outline an important innate immunity element responsive to viral infection and IFN-I signaling in both AD and COVID-19.

Keywords

• Alzheimer's disease
• Antimicrobial protection hypothesis
• COVID-19
• FYN Kinase
• IFITM3
• Type I Interferon