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Research into the pathophysiology behind coronavirus disease 2019 (COVID-19), caused by coronavirus 2 (SARS-CoV-2) infection of severe acute respiratory syndrome, is ongoing. A team of researchers from Columbia University Vagelos College of Physicians & Surgeons, USA, presents findings linking oxidative stress and activation of a biochemical pathway associated with Alzheimer’s disease to SARS infection -CoV-2.
“In this study, we propose a potential mechanism that could contribute to systemic organ failure caused by SARS-CoV-2: Ca defective2+ regulation and its downstream signaling, ”the researchers wrote. “It is particularly interesting to note that the leaky RyR2 channels in the brain were associated with the activation of neuropathological pathways that are also found in the brains of patients with Alzheimer’s disease.”
The study “Alzheimer-like remodeling of the neuronal ryanodine receptor in COVID-19” is available as a preprint on the bioRxiv* server, while the article is subject to peer review.
Evidence of oxidative stress in patients with COVID-19
The team collected heart, lung and brain tissue from autopsied patients who had succumbed to COVID-19. They measured the ratio of glutathione disulfide to glutathione. Their results showed significantly higher oxidative stress in all three organs compared to controls.
By measuring the phosphorylation of SMAD3, the downstream signal of TGF-β, the researchers found that infection with SARS-CoV-2 increased the levels of phosphorylated SMAD3 in all three organs. The authors suggest that SARS-CoV-2 increases TGF-β. In addition, increased cytokine signaling activity was present in brain tissue, suggesting that SARS-CoV-2 activation of the TGF-β pathway was widespread.
Oxidative stress induced by COVID-19 blocks apoptosis of cells infected with the virus
The 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 body. The increase in NOX2 binding was associated with the ryanodine receptor (RyR) / intracellular calcium release channel.
This chain of events, in particular with the SMAD3 proteins involved in TGF-β signaling, blocked the ability to self-destruct in cells infected with the virus. The researchers also found that the N protein in SARS-CoV-2 infection interacted directly with SMAD3 to encourage this action.
As a result, apoptosis of host cells infected with SARS-CoV-2 is blocked and the formation of tissue fibrosis is promoted, especially in the lungs, thus contributing to respiratory distress and consequent pulmonary failure associated with the disease. disease, ”the researchers wrote.
While the direct interaction with N and SMAD3 has been found in the heart and lungs of individuals with SARS-CoV-2 infection, it was absent in the brain. The authors suggest that increased inflammation and an oxidative response indirectly affect the neurological changes seen in COVID-19.
RyR channel COVID-19 induced changes are reversible
The increased binding of NOX2 to RyR2 may have altered the RyR channel. The team looked at this up to 3[H]binding to ryanodine, which only binds 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 the RyR channels open during physiological resting conditions when the channels need to be closed. The decrease in duct closure causes calcium leakage, which the authors say contributes to the pathophysiology of many other diseases.
For example, the team suggests that altered calcium signaling in the RyR channel likely contributes to neurological and cardiovascular diseases such as cardiomyopathies and arrhythmias.
Despite the structural changes to the channel, the addition of the Rycal drug, ARM210, corrected calcium leakage by linking calstabin2 to RyR2.
Long-term effects of COVID-19 share a similar path with Alzheimer’s disease
Leakage of RYR channels has already contributed to Alzheimer’s and Huntington’s disease. When the researchers analyzed brain samples from infected individuals, they found increased phosphorylation of AMPK and GSK 3ß, which caused Tau hyperphosphorylation in SARS-CoV-2. Specifically, brain samples infected with SARS-CoV-2 exhibited higher Tau phosphorylation at S199 and S202 / T205. The authors say that excessive tau levels are similar to Alzheimer’s Tau pathology.
The team also found increased expression of p25, which activates CDK5 – a neurotoxic activator of amyloid precursor protein processing seen in Alzheimer’s disease. However, it is important to note that the increased expression of kinase and p25 did not directly lead to Alzheimer’s disease as there was no activation of the amyloid-beta pathway. .
The researchers suggest that the neurophysiological changes associated with COVID-19 could explain the symptom of “brain fog” seen in some patients recovering from the virus.
We also demonstrate that infection with SARS-CoV-2 113 activates biochemical pathways related to tau pathology associated with AD and that leaky calcium channels can be a potential therapeutic target for respiratory, cardiac and neuronal complications 115 associated with COVID-19 ”. the researchers concluded.
*Important Notice
bioRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or treated as established information.
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