COVID-19 Induced Oxidative Stress Can Lead To Systemic Organ Failure While Long COVID Also Exhibits Pathway That Leads To Alzheimer’s Disease!

Researchers from Department of Physiology and Cellular Biophysics at the Clyde and Helen Wu Center for Molecular & Cardiology- Columbia University Vagelos College of Physicians & Surgeons, New York have in a news study discovered that systemic organ failure in COVID-19 disease is basically caused by oxidative stress while alarming they also found that evidence linking oxidative stress and the activation of a biochemical pathway associated with Alzheimer’s disease to SARS-CoV-2 infection hence explaining certain neurological conditions manifested by both COVID-19 and Long COVID patients.


 
According to the study abstract,”COVID-19, caused by the SARS-CoV-2 coronavirus involves multiple organs including cardiovascular, pulmonary and central nervous system. Understanding how SARS-CoV-2 infection afflicts diverse organ systems remains challenging. Particularly vexing has been the problem posed by persistent organ dysfunction known as “long COVID,” which includes cognitive impairment. Here the study team provides evidence linking SARS-CoV-2 infection to activation of TGF-ß signaling and oxidative overload. One consequence is oxidation of the ryanodine receptor/calcium (Ca2+) release channels (RyR) on the endo/sarcoplasmic (ER/SR) reticuli in heart, lung and brains of patients who succumbed to COVID-19. This depletes the channels of the stabilizing subunit calstabin2 causing them to leak Ca2+ which can promote heart failure, pulmonary insufficiency and cognitive and behavioral defects. Ex-vivo treatment of heart, lung, and brain tissues from COVID-19 patients using a Rycal drug (ARM210)10 prevented calstabin2 loss and fixed the channel leak. Of particular interest is that neuropathological pathways activated downstream of leaky RyR2 channels in Alzheimer ’s disease (AD) patients were activated in COVID-19 patients. Thus, leaky RyR2 Ca2+ channels may play a role in COVID-19 pathophysiology and could be a therapeutic target for amelioration of some comorbidities associated with SARS-CoV-2 infection.”
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.02.18.431811v1
 
Studies looking at the pathophysiology behind COVID-19 disease, caused by the SARS-CoV-2 coronavirus infection, is ongoing.
 
The study team presented results linking oxidative stress and the activation of a biochemical pathway associated with Alzheimer’s disease to SARS-CoV-2 infection.
 
Corresponding author Dr Andrew R Marks from the Department of Physiology and Cellular Biophysics-Columbia University told Thailand Medical News, “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. 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.”
 
Oxidative Stress in COVID-19
 
The study 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.
 
Also by measuring SMAD3 phosphorylation, the downstream signal for TGF-β, the study team found SARS-CoV-2 infection increased phosphorylated SMAD3 levels in all three organs.
 
The team suggests 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.
 
Oxidative Stress Blocks Apoptosis Of SARS-CoV-2 Virus-Infected Cells
 
It was found that 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.
 
Importantly 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 study team also found the N protein in SARS-CoV-2 infection directly interacted with SMAD3 to encourage this action.
 
Hence, 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.
 
However although 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.
 
Alterations To The Ryr Channel Is Reversible
 
It was noted that the increased NOX2 binding to RyR2 may have modified the RyR channel. The study 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 researchers 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 team says contributes to many other diseases' pathophysiology.
 
For example, the study team suggests the altered calcium signaling in the RyR channel likely contributes to neurological and cardiovascular diseases such as cardiomyopathies and arrhythmias.
 
Also despite the channel's structural alterations, adding the Rycal drug, ARM210, fixed the calcium leak by rebinding calstabin2 to RyR2.
 
Alarmingly Long COVID-19 Effects Share Similar Pathway With Alzheimer’s Disease
 
It must be noted that leaking RYR channels has previously contributed to Alzheimer’s and Huntington’s disease.
 
Upon analyzing brain samples from infected individuals, the study team 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 study team says the excess tau levels are similar to the Alzheimer Tau pathology.
 
The study 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 team suggests the neurophysiological changes associated with COVID-19 could explain the ‘brain fog’ symptom seen in some patients who recover from the virus.
 
Dr Marks concluded, “We also demonstrate that SARS-CoV-2 infection activates biochemical pathways linked to the tau pathology associated with Alzheimer’s disease and that leaky calcium channels may be a potential therapeutic target for the respiratory, cardiac, and neuronal complications associated with COVID-19.”
 
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