A Peek into Pandora's Box: COVID-19 and Neurodegeneration

Abstract

Ever since it was first reported in Wuhan, China, the coronavirus-induced disease of 2019 (COVID-19) has become an enigma of sorts with ever expanding reports of direct and indirect effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on almost all the vital organ systems. Along with inciting acute pulmonary complications, the virus attacks the cardiac, renal, hepatic, and gastrointestinal systems as well as the central nervous system (CNS). The person-to-person variability in susceptibility of individuals to disease severity still remains a puzzle, although the comorbidities and the age/gender of a person are believed to play a key role. SARS-CoV-2 needs angiotensin-converting enzyme 2 (ACE2) receptor for its infectivity, and the association between SARS-CoV-2 and ACE2 leads to a decline in ACE2 activity and its neuroprotective effects. Acute respiratory distress may also induce hypoxia, leading to increased oxidative stress and neurodegeneration. Infection of the neurons along with peripheral leukocytes' activation results in proinflammatory cytokine release, rendering the brain more susceptible to neurodegenerative changes. Due to the advancement in molecular biology techniques and vaccine development programs, the world now has hope to relatively quickly study and combat the deadly virus. On the other side, however, the virus seems to be still evolving with new variants being discovered periodically. In keeping up with the pace of this virus, there has been an avalanche of studies. This review provides an update on the recent progress in adjudicating the CNS-related mechanisms of SARS-CoV-2 infection and its potential to incite or accelerate neurodegeneration in surviving patients. Current as well as emerging therapeutic opportunities and biomarker development are highlighted.

Keywords: COVID-19; SARS-CoV-2; biomarker; mitochondria; neurodegeneration; therapeutics.

Figure 1

Schematic representation of SARS-CoV-2 entry routes. (A) SARS-CoV-2 enters the nasal cavity via droplets. It subsequently enters the blood through nasal submucosa. It may further obtain access to the olfactory nerves and, thus, the olfactory bulb by moving upstream. SARS-CoV-2 enters the lungs, crosses the thin alveolar membrane, and enters the blood to access all organs, including the brain. (B) SARS-CoV-2 binds to ACE2 receptor and gains entry into endothelial cells, infects, and replicates in cells of neuronal origin, leading to inflammation and opening of the BBB. Inflammation then spreads to vascular mural cells and other brain cells, such as microglia and astrocytes. The resulting alteration in neuronal function and inflammation results in encephalopathy in COVID-19. (C) Another possible way that SARS-CoV-2 could gain entry into the brain is through blood–CSF (B–CSF) barrier by binding to the ACE2 receptor in choroid plexus epithelium.