Research looking at the pathophysiology behind coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is ongoing. A team of researchers from Columbia University Vagelos College of Physicians & Surgeons, USA, present results linking oxidative stress and the activation of a biochemical pathway associated with Alzheimer’s disease to SARS-CoV-2 infection.
“In this study, we propose a potential mechanism that may contribute to systemic organ failure caused by SARS-CoV-2: defective Ca2+ regulation and its downstream signaling,” wrote the researchers. “Of particular interest is that leaky RyR2 channels in the brain were associated with activation of neuropathological pathways that are also found in the brains of Alzheimer’s Disease patients.”
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
The study "Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19" is available as a preprint on the bioRxiv* server, while the article undergoes peer review.
Evidence of oxidative stress in patients with COVID-19
The team collected heart, lung, and brain tissues from autopsied patients who had succumbed to COVID-19. They measured the ratio of glutathione disulfide to glutathione. Their results showed significantly more oxidative stress in all three organs compared to controls.
By measuring SMAD3 phosphorylation, the downstream signal for TGF-β, the researchers found SARS-CoV-2 infection increased phosphorylated SMAD3 levels in all three organs. The authors suggest this SARS-CoV-2 increased TGF-β. In addition, increased activity of cytokine signaling was present in brain tissues suggesting SARS-CoV-2 activation of the TGF-β pathway was widespread.
COVID-19-induced oxidative stress blocks apoptosis of virus-infected cells
Increased oxidative stress results in a snowball effect from the activation of the TGF-β signaling pathway to an increased presence of NOX2 in the heart, lung, and brain tissues of individuals with SARS-CoV-2 in their bodies. The increased NOX2 binding was associated with the ryanodine receptor (RyR)/intracellular calcium release channel.
This chain of events, especially with the SMAD3 proteins involved with TGF-β signaling, blocked the ability to self-destruct in virus-infected cells. The researchers also found the N protein in SARS-CoV-2 infection directly interacted with SMAD3 to encourage this action.
As a result, apoptosis of SARS-CoV-2 infected host cells is blocked and formation of tissue fibrosis is promoted, especially in lung, thus contributing to the respiratory distress and subsequent pulmonary failure associated with the disease,” wrote the researchers.
While the direct interaction with N and SMAD3 was found in the heart and lungs of individuals with SARS-CoV-2 infection, it was absent in the brain. The authors suggest increased inflammation and oxidative response indirectly affect the neurological changes observed in COVID-19.
COVID-19-induced alterations to the RyR channel is reversible
The increased NOX2 binding to RyR2 may have modified the RyR channel. The team looked at this by the amount of 3[H]ryanodine binding, which binds only to the open state of the RyR channel, present in the heart, lungs, and brain tissue of infected individuals.
The team found abnormally high activity with RyR channels open during physiological resting conditions when channels should be closed. The decreased closing of the channel causes a calcium leak, which the authors say contributes to many other diseases' pathophysiology.
For instance, the team suggests the altered calcium signaling in the RyR channel likely contributes to neurological and cardiovascular diseases such as cardiomyopathies and arrhythmias.
Despite the channel's structural alterations, adding the Rycal drug, ARM210, fixed the calcium leak by rebinding calstabin2 to RyR2.
Long COVID-19 effects share similar pathway with Alzheimer’s disease
Leaking RYR channels has previously contributed to Alzheimer’s and Huntington’s disease. When researchers analyzed brain samples from infected individuals, they found increased AMPK and GSK 3ß phosphorylation, which caused hyperphosphorylation of Tau in SARS-CoV-2. Specifically, SARS-CoV-2 infected brain samples displayed higher Tau phosphorylation at S199 and S202/T205. The authors say the excess tau levels are similar to the Alzheimer Tau pathology.
The team also found increased p25 expression, which activates CDK5 — a neurotoxic activator of the amyloid precursor protein processing observed in Alzheimer’s disease. However, it’s important to note that the increased kinase and p25 expression did not directly lead to Alzheimer’s as there was no activation of the amyloid-beta pathway.
The researchers suggest the neurophysiological changes associated with COVID-19 could explain the ‘brain fog’ symptom seen in some patients who recover from the virus.
We also demonstrate that SARS-CoV-2 infection 113 activates biochemical pathways linked to the tau pathology associated with AD and that leaky calcium channels may be a potential therapeutic target for the respiratory, cardiac, and neuronal 115 complications associated with COVID-19,” concluded the researchers.
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Article Revisions
- Apr 7 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
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