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.

COVID-19-Associated Encephalopathy (COVEP): Basic Aspects of Neuropathology

“…Given the mechanisms described so far and their inevitable neuronal degeneration and necrosis spectrum of sequelae, they are predominantly the ones occurring in severe and fatal cases [26,68,89]. Accumulating evidence suggests additional mechanisms associated with SARS-CoV-2 infection that could trigger or accelerate already-developed neurodegenerative disorders [117,118].…”

“…Some studies suggest that the viral surface structure acts as a binding site for heparin and accelerates the aggregation and displacement of heparin-binding proteins such as Aβ, α-synuclein, tau, prion, and TDP-43 RRM, resulting in initiation or acceleration of the associated neurodegenerative pathways [119,120]. Other studies have also suggested that within the host cells, the SARS-CoV-2 viral protein interacts with multiple intracellular pathways associated with aging, taking part in vesicle trafficking, lipid modifications, RNA processing and regulation, ubiquitin ligases, and mitochondrial activity, while at the same time depleting intracellular iron and further hindering mitochondrial function [59,60,117]. Furthermore, as the virus enters the host cell through the ACE-2 receptor, viral interaction may lead to decreased functionality, reducing the neuroprotective effects of ACE-2 [121,122].…”

“…Multiple case reports and cohort studies have reported a significant functional and cognitive decline in these patients, with these patients also being more likely to expire from COVID-19 [124,125]. The exact mechanism of accelerated degeneration in these patients is also highly disputed, with some studies supporting the direct neuroinvasive potential of SARS-CoV-2 and pointing toward the brainstem as the most affected area in the encephalitis spectrum; others propose an ACE-2 suppression-associated mechanism, as the receptor is significantly expressed in dopaminergic neurons, while others point to the fact that infection-associated acceleration in Parkinson's disease is a typical hallmark of the disease and that progressive decline in these patients is predominantly due to physical and other therapies being discontinued during lockdowns [117,[124][125][126][127][128]. One further fact supporting these claims is the isolation of coronavirus antibodies against other members of the viral family from the cerebrospinal fluid of patients with Parkinson's disease in the past decades [128,129].…”

“…Furthermore, discontinuation of non-medication treatment and social isolation during lockdowns has been shown to have adverse functional effects, not only on patients with chronic diseases, including neurodegenerative ones such as Alzheimer's disease, but significantly on neuropsychiatric diseases such as depression, anxiety, and post-traumatic stress disorder [117].…”

Impact of the Renin-Angiotensin System on the Pathogeny and Pharmacotherapeutics of Neurodegenerative Diseases

“…Several lines of evidence suggest that the neurological aspects of long COVID may point toward degeneration of neural targets [ 215 ]. ACE implication may be of interest because SARS-CoV-2 infection can impair the disassembly of host stress granules (SGs) and promote the aggregation of SG-related amyloid proteins, which may lead to an increased risk of neurodegeneration [ 216 ].…”