Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment
Preprint
- 22 March 2021
- preprint
- research article
- Published by Cold Spring Harbor Laboratory
Abstract
Background: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions.Methods: In this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2.Results: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSGandFURIN) and antiviral defense genes (LY6E,IFITM2,IFITM3, andIFNAR1) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk alleleAPOEE4/E4 displayed reduced levels of antiviral defense genes compared toAPOEE3/E3 individuals.Conclusion: Our results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.Keywords
Other Versions
- Published version: Version Alzheimer's Research & Therapy, 13, preprints
This publication has 113 references indexed in Scilit:
- MINT, the molecular interaction database: 2012 updateNucleic Acids Research, 2011
- PINA v2.0: mining interactome modulesNucleic Acids Research, 2011
- Vascular Cell Adhesion Molecule-1 Expression and Signaling During Disease: Regulation by Reactive Oxygen Species and AntioxidantsAntioxidants and Redox Signaling, 2011
- Phospho.ELM: a database of phosphorylation sites--update 2011Nucleic Acids Research, 2010
- edgeR: a Bioconductor package for differential expression analysis of digital gene expression dataBioinformatics, 2009
- Human Protein Reference Database--2009 updateNucleic Acids Research, 2008
- Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral responseNature, 2005
- Towards a proteome-scale map of the human protein–protein interaction networkNature, 2005
- New insights into TGF-β–Smad signallingTrends in Biochemical Sciences, 2004
- Human Gene Mutation Database (HGMD®): 2003 updateHuman Mutation, 2003