Working Paper Communication Version 2 This version is not peer-reviewed

FYN, SARS-CoV-2, and IFITM3 in the Neurobiology of Alzheimer’s Disease: A Regulatory Feedback Loop Governing Tau and Aβ Pathology

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.; Mavridis, T.; 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 Vavougios, G.; Breza, M.; Mavridis, T.; 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

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-mediated FYN/IFITM3 induction would mechanistically result in increased Tau fibrilization and Aβ oligomerization. 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.

Subject Areas

IFITM3; SARS-CoV-2; FYN; SRC Kinases; Alzheimer's Disease

Comments (1)

Comment 1
Received: 2 February 2021
Commenter: George Vavougios
Commenter's Conflict of Interests: Author
Comment: In this revised version, we have added significant concurrent studies that support our model. We furthermore elaborate on IFITM3's/FYN interaction within the setting of an endocytosis signal, and the resulting tauopathy / Beta Amyloid oligomerization within the framework of an innate immune response.Please note that following extensive revisions and updates of the main manuscript, Dr Theodore Mavridis has replaced Dr Nikou as an author, at her request. 
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