Version 1
: Received: 25 December 2020 / Approved: 29 December 2020 / Online: 29 December 2020 (16:47:37 CET)
Version 2
: Received: 1 February 2021 / Approved: 2 February 2021 / Online: 2 February 2021 (09:56:41 CET)
How to cite:
Vavougios, G.; Breza, M.; Nikou, S.; Krogfelt, K. FYN, SARS-CoV-2, and IFITM3 in the Neurobiology of Alzheimer’s Disease: A Regulatory Feedback Loop Governing Tau and Aβ Pathology. Preprints2020, 2020120739. https://doi.org/10.20944/preprints202012.0739.v1
Vavougios, G.; Breza, M.; Nikou, S.; Krogfelt, K. FYN, SARS-CoV-2, and IFITM3 in the Neurobiology of Alzheimer’s Disease: A Regulatory Feedback Loop Governing Tau and Aβ Pathology. Preprints 2020, 2020120739. https://doi.org/10.20944/preprints202012.0739.v1
Vavougios, G.; Breza, M.; Nikou, S.; Krogfelt, K. FYN, SARS-CoV-2, and IFITM3 in the Neurobiology of Alzheimer’s Disease: A Regulatory Feedback Loop Governing Tau and Aβ Pathology. Preprints2020, 2020120739. https://doi.org/10.20944/preprints202012.0739.v1
APA Style
Vavougios, G., Breza, M., Nikou, S., & Krogfelt, K. (2020). FYN, SARS-CoV-2, and IFITM3 in the Neurobiology of Alzheimer’s Disease: A Regulatory Feedback Loop Governing Tau and Aβ Pathology. Preprints. https://doi.org/10.20944/preprints202012.0739.v1
Chicago/Turabian Style
Vavougios, G., Sofia Nikou and Karen Krogfelt. 2020 "FYN, SARS-CoV-2, and IFITM3 in the Neurobiology of Alzheimer’s Disease: A Regulatory Feedback Loop Governing Tau and Aβ Pathology" Preprints. https://doi.org/10.20944/preprints202012.0739.v1
Abstract
Introduction IFITM3, an innate immune protein linked to COVID-19 severity, has recently been identified as a novel γ-secretase modulator. Independent research has shown that IFITM3 may facilitate SARS-CoV-2 neurotropism in an ACE2-independent manner. 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 / IFITM3 / AD interplay, validating previous findings from our group. 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. Discussion 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 Aβ production. FYN recruitment by viral processes results in abrogation of both fusion of IFITM3 vesicles with lysosomes; immunoevasion, by FYN-mediated impairment of autophagy would then serve to promote impaired detoxification from Aβ, while propagating Tau pathology in an IFITM3-independent manner.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
