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Advanced Neurology SARS-CoV-2 in age-associated neurodegeneration

the CNS, but it is worth hypothesizing that even if the associated with neurodegenerative diseases. By triggering
viral genome is not present in the brain, viral remnants key events such as chronic inflammation, oxidative stress,
may create a degenerative environment that could be impaired proteostasis, and other aging-like processes,
associated with long-term COVID symptoms. Although the virus can accelerate the onset and progression of
the functions of SARS-CoV-2 proteins are well described diseases such as Alzheimer’s and Parkinson’s diseases. 82,86
in the literature, there is a lack of insights into how Understanding these mechanisms underscores the
individual SARS-CoV-2 proteins modulate the immune importance of addressing the long-term consequences in
response in neurons, glial cells, and astrocytes (Table 3). COVID-19 patients and reinforces the need for targeted
An emerging theory is that acute inflammation in therapeutic strategies to mitigate these effects.
alveolar epithelial cells may contribute to neurological
consequences, suggesting communication between 6.1. Chronic inflammation and COVID-19: Enduring
organs. However, the available evidence is insufficient to fire in the brain
confirm this phenomenon, and further investigation is The pathophysiology of PASC, particularly its association
needed to identify the unique viral signaling pathways with neurological sequelae after mild or moderate
that contribute to these outcomes. SARS-CoV-2 infection, is still largely unexplored. One
of the simplest explanations for accelerated age-related
6. SARS-CoV-2 persistence in the context of neurodegeneration in PASC is chronic neuroinflammation.
the aging microenvironment in the brain The viral persistence of the virus can trigger prolonged
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Viral infections are increasingly being recognized as inflammatory responses in the brain. Interaction with
important contributors to the development of neurological specific receptors activates brain cells – including neurons,
disorders, with growing evidence suggesting they can oligodendrocytes, and microglia – which amplifies immune
mimic the aging microenvironment in the brain. This signaling and leads to the release of pro-inflammatory
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phenomenon involves several key processes that overlap cytokines such as interleukin (IL)-1β, tumor necrosis
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with the biological mechanisms of aging, including factor (TNF)-α, and IL-6. COVID-19 brains have
chronic inflammation, oxidative stress, mitochondrial shown degeneration and extensive inflammation, even in
dysfunction, impaired proteostasis, epigenetic alterations, individuals without neurological symptoms, and overlap
cellular senescence, and gut-brain dysbiosis 8,78-80 (Figure 4). has been observed between AD marker genes and genes
These processes are associated with the most prevalent upregulated during COVID-19 infection. Inflammatory
neurodegenerative diseases, including AD, Parkinson’s biomarkers such as TNF, IL-6, IL-1, complement proteins,
disease, amyotrophic lateral sclerosis, stroke, and several and galectin-3 have been proposed as common prognostic
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other neuropathies. 79,81 Recent reports suggest that biomarkers for both SARS-CoV-2 infection and AD. In
SARS-CoV-2 infection may exacerbate protein aggregation, addition, viral infection can activate the brain’s resident T
particularly amyloid-beta (Aβ) peptides and α-synuclein, lymphocytes, further increasing neuroinflammation and
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which are major pathogenic hallmarks of AD and neurodegeneration, thereby accelerating brain aging. In
Parkinson’s disease. Furthermore, it has been suggested individuals with long COVID, T-cell alterations have been
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that the apolipoprotein E gene (APOE4), a significant risk found, including an increased population of exhausted
+
+
factor for AD, could also serve as a biomarker for severe T cells, decreased numbers of CD4 and CD8 effector
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COVID-19. Specifically, the type 4 allele of the gene memory cells, and increased expression of programmed
(APOE ɛ4) is a major susceptibility factor for both AD death-1 on central memory cells, persisting for at least
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and COVID-19. Research has shown that the APOE 13 months. Type I and type II IFNs also persist for at least
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genotype influences susceptibility to or resistance against 8-month post-infection. Infected individuals with long
pathogens in various infectious diseases. The protein COVID also exhibit increased non-classical monocytes,
products of the APOE cluster genes may even function as activated B cells, double-negative B-cells, and elevated
receptors for SARS-CoV-2, as they have been identified levels of IL-4 and IL-6, while the number of conventional
as receptors for several viruses, including herpesvirus immune cells decreases. In conjunction with these
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and hepatitis C virus. This attribute has been observed T-cell changes, patients with PASC show a dysregulated
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in both acute and mild cases of COVID-19. Moreover, the pro-inflammatory cytokine profile in their blood, with
persistence of COVID-19 in the brain coincides with the increased levels of IL-1β, IL-6, and TNF-α-cytokines
features of pathological aging, potentially contributing to known to increase in the aging brain. 87,88 A contemporary
long-term neurological sequelae. Overall, SARS-CoV-2 study by Ng et al. has demonstrated that IFN-β has
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infection not only mimics the aging microenvironment a profound effect on viral persistence. While IFN-α
in the brain but also exacerbates the pathological features controls early viral spread, blocking of IFN-β improves
Volume 3 Issue 4 (2024) 9 doi: 10.36922/an.4267