Converging pathomechanisms link SARS-CoV-2 infection with major neurodegenerative diseases

Abstract

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, functional alteration of the blood–brain barrier (BBB), neuroinflammatory processes, mitochondrial dysfunction and pathological protein aggregation, all of which are central to the pathogenesis of major neurodegenerative diseases. 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 and validate the potential mechanistic links. We propose 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 might be another important factor driving the future burden of the most common neurodegenerative diseases. Schematic illustrating the potential link between the progression from SARS-CoV-2 infection and immune dysregulation to the development of Long COVID and eventually the subsequent onset of major neurodegenerative diseases (e.g., Parkinson's disease and Alzheimer's disease).