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

Vavougios, G.; Breza, M.; Nikou, S.; Krogfelt, K.

Background and aims: In a previous study, we had detected perturbations in IFITM3 networks in both the CNS and peripheral immune cells donated by AD patients.The purpose of this study is to explore the transcriptomic evidence of the SARS-CoV-2-AD interplay by exploring perturbations in FYN and IFITM3 gene expression. Methods: Exploratory analyses involved meta-analysis of bulk and single cell RNA data for IFITM3 and FYN differential expression. For confirmatory analyses, we performed gene set enrichment analysis (GSEA) on an AD gene signature from AD Consensus transcriptomics;using the Enrichr platform, we scrutinized COVID-19 datasets for significant, overlapping enriched biological networks. Results: Bulk RNA data analysis revealed that IFITM3 and FYN were differentially expressed in two CNS regions in AD: the temporal cortex (AD vs. Controls, adj.p-value=1.3e-6) and the parahippocampal cortex (AD vs. controls, adj.p-value=0.012). Correspondingly, single cell RNA analysis of IFITM3 and FYN revealed that it was differentially expressed in neuronal cells donated from AD patients (astrocytes, microglia and oligodendrocyte precursor cells), when compared to controls. Conclusion: IFITM3 and by extent FYN were found as interactors within biological networks overlapping between AD and SARS-CoV-2 infection. SARS-CoV-2 SARS-CoV-2-mediated IFITM3 induction would mechanistically result in increased A production. FYN recruitment by viral processes results in abrogation of both fusion of IFITM3 vesicles with lysosomes;immunoevasion, by FYNmediated impairment of autophagy would then serve to promote impaired detoxification from A, while propagating Tau pathology in an IFITM3-independent manner.