Study links COVID-19 inflammatory manifestations in brain lysates to Alzheimer’s Disease markers

By Sreetama Dutt M.Sc.Reviewed by Aimee MolineuxFeb 7 2022

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause pulmonary damage. A severe form of the disease causes long-term sequelae that may also lead to cardiovascular and neurological damage.

It has been observed that one-third of patients with COVID-19 develop neurological symptoms that include headaches, odd sensations like burning or pricking needles in the body, syncope, dizziness, confusion, and seizures. Such sequelae can also lead to swelling of the brain tissue, encephalitis, stroke, and neuronal degeneration.

Background

Recent studies have shown the presence of diffused inflammatory markers in the brain cells of >80% of COVID-19 patients that can cause potentially serious neurological complications. Early-stage Alzheimer’s Disease (AD) manifests with hyposmia (loss of smell), also common to COVID-19 patients. Moreover, type II astrocytosis, common with AD pathology, has been reported in neurological studies with COVID-19 patients.

SARS-CoV-2 enters the human system through the Angiotensin Converting Enzyme (ACE2) receptors which are also expressed in the brain stem, the thermal center, and cortex of the brain, making them more susceptible to infection. In studies exploring severe SARS-CoV-2 infections and/or symptoms, the role of upregulated levels of TGF-β (an inflammatory cytokine) has been linked to reduced ACE2 activity and vice-versa. Previous studies have shown that increased TGF-β activity caused by oxidative stress can potentially lead to post-translational modifications of the ryanodine receptor (RyR) channels causing intracellular calcium (Ca²⁺) channel leaks, leading to mitochondrial Ca²⁺ overload and dysfunction. COVID-19, on the other hand, has also been shown to cause increased TGF-β activity and mitochondrial dysfunction.

Interestingly, reduced ACE2 activity has also been studied in patients with AD and has been linked to hyperphosphorylation of the tau protein and increased amyloid-beta (Aβ) pathology in pre-clinical studies. Deeper insights into any possible link between reduced ACE2 activity and increased TGF-β and tau signaling in the context of SARS-CoV-2 infection can point to possible similarities in COVID-19 and AD pathologies.

Researchers recently published a study in Alzheimer’s & Dementia exploring this link between the body’s inflammatory response to SARS-CoV-2 infection within the neuropathological pathways and tau hyperphosphorylation.

About the study

For this study, researchers obtained de-identified tissues from the heart, lung, and brain tissue (including cortex and cerebellum samples) for 10 patients from the COVID BioBank at Columbia University. The study population was analyzed on the basis of two major categories – the younger patient group (≤ 58 years old) and the older patient group (≥ 66 years old) to record the normal, age-dependent changes in Amyloid Precursor Protein (APP) and tau pathology.

To this end, researchers monitored oxidative stress levels in the cortex (Ctx) and cerebellum (CB) tissues from COVID-19 patients and controls by measuring the ratio of glutathione disulfide [GSSG] to glutathione [GSH] using an Enzyme-Linked Immunosorbent Assay (ELISA) technique. COVID-19 patients had significant oxidative stress with a 3.8- and 3.2-fold increase in GSSG/GSH ratios in the Ctx and CB compared to controls, respectively.

A striking observation was the upregulation of Protein Kinase A (PKA) and calmodulin-dependent protein kinase II (CaMKII) activity, which have been correlated with cortical tau hyperphosphorylation in AD patients. Furthermore, increased AMPK and GSK3β phosphorylation (both of which are responsible for phosphorylating Tau in AD) in both Ctx and CB samples in SARS-CoV-2–infected brains led to hyperphosphorylation of the pivotal tau protein. Among older patients, tau phosphorylation was increased at S199, S202, S214, S262, and S356, while younger patients showed the same at S214, S262, and S356, both correlating with AD pathology. Normal APP processing was observed in COVID-19 brain lysates whereas abnormal APP processing was only observed in AD patients.

Evidence of systemic activation and upregulation of TGF-β in brain lysates of COVID-19 patients was obtained measuring an increase in SMAD3 phosphorylation. This upregulation of TGF-β signaling caused an increase in the RyR2 and (calstabin2 or NADPH oxidase 2) NOX2 levels in COVID-19 Ctx and CB samples.

Considering the increased levels of oxidative stress and increased NOX2 binding to RyR2 seen in COVID-19 brains, researchers further investigated the post-translational modifications. This investigation showed remodeling of the RyR2 pathway owing to increased PKA phosphorylation on serine 2808, and depletion of the stabilizing protein subunit calstabin2 (NOX-2), causing the RyR2 channel to leak Ca²⁺ in mitochondria. This leak and the resulting dysfunctionality of the mitochondria were consistent with the pathophysiology of AD.

Implications

The study results establish a correlation between AD and COVID-19 in terms of inflammatory markers and hyperphosphorylation of the tau protein.

It also projects the leaky Ca²⁺ RyR2 channels to be a possible therapeutic target for protecting against cognitive and neurological defects associated with severe SARS-CoV-2 infection and long COVID-19 sequelae.