Converging Pathomechanisms Link SARS-CoV-2 Infection With Major Neurodegenerative Diseases

Background: Neurological complications are among typical clinical manifestations, both during the acute phase of SARS-CoV-2 infection and long-term post-acute COVID-19 sequelae, i.e., Long COVID. A growing body of evidence connects SARS-CoV-2 infection to systemic inflammation, peripheral immune dysregulation, blood-brain barrier (BBB) dysfunction, neuroinflammatory processes, mitochondrial dysfunction and pathological protein aggregation, all of which are central to the pathogenesis of major neurodegenerative diseases.

Main Body: In this review, we discuss the converging shared underlying molecular mechanisms that link the ‘acute’ SARS-CoV-2 infection that often only lasts for days and ‘chronic’ neurodegenerative diseases that often take decades to develop. We further review human induced pluripotent stem cells (iPSCs)-derived brain organoid and BBB models for Parkinson’s disease (PD) and Alzheimer’s disease (AD) as well as artificial intelligence (AI)-facilitated knowledge graph methods that are used to hypothesize, discover and validate the potential mechanistic links.

Conclusions: We suggest that besides the established links between viral infections and neurodegenerative or neuroinflammatory conditions, such as Epstein-Barr virus (EBV) in multiple sclerosis or herpes zoster in AD, SARS-CoV-2 infection is another important factor defining the future burden of the most common neurodegenerative diseases.