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

Systematic analyses of various studies and case reports and cells in the gastrointestinal (GI) tract. 48,49 Study has
suggest that SARS-CoV-2 not only alters brain architecture demonstrated that among respiratory viruses, SARS-CoV-2
but also causes cognitive impairment in individuals with exhibits the highest affinity for the ACE2 receptor. This
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mild or acute COVID-19 infection. Previous reports have unique feature of SARS-CoV-2 enhances neuroinvasion
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demonstrated traces of SARS-CoV-2 in the human brain; and viral persistence in the brain. Host proteases such
however, COVID-19 can induce physiological changes in as transmembrane serine protease 2, cathepsin L, and
the brain even without direct viral presence. 17,19 While most furin are involved in the cleavage of the spike protein.
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reports recognize the significant impact of SARS-CoV-2 on In addition, the neuronal co-receptor neuropilin-1 can
brain architecture, there remains a limited understanding facilitate viral internalization. 52
of how these structural changes interact with the aging Following primary infection, SARS-CoV-2 can disrupt
process. Therefore, we highlight a key hypothesis related to
the mechanisms underlying the neurological consequences the epithelial barrier and invade the bloodstream, where
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caused by long COVID (Table 1). it may persist before reaching the CNS. Neuroinvasion
through the bloodstream has also been described for other
4. Neuroinvasion: The beginning of viral coronaviruses, such as Middle East respiratory syndrome
persistence coronavirus (MERS-CoV), which enters the bloodstream
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and subsequently infects endothelial cells. Paniz-Mondolfi
Brain cells are extremely selective and allow only et al. observed SARS-CoV-2-like particles in endothelial
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specific candidates to enter. Neuroinvasion is a crucial cells, pericytes in brain capillaries, and astrocyte processes,
step that ensures the persistence of the virus in the supporting the hypothesis of hematogenous endothelial
brain. 43,44 Neurovirulent viruses, including members of neuroinvasion of SARS-CoV-2. The virus can infect the
the Coronaviridae family, employ multiple routes for endothelial cells at the blood–CSF barrier and subsequently
neuroinvasion (Figure 2). Two crucial pathways for CNS spread into the CNS. 48,54 In addition, circumventricular
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penetration are the hematogenous route and the neuronal cerebral organs and the choroid plexus, which are not
route. In addition, the olfactory route plays a critical protected by the BBB, could serve as entry points for viral
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role in CNS penetration. Pathways such as the nasal penetration. In acute infections, cytokine release or a
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epithelium route, lymphatic tissue, and CSF infection may cytokine storm can alter BBB permeability, particularly by
also play significant roles. 47 disrupting tight junctions, allowing virus particles to enter
The first established theory of SARS-CoV-2 invasion the brain. Recent findings have shown evidence of BBB
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into the brain involves the host ACE2 receptor, which is disruption during acute COVID-19 infection and in long
present at the surface of alveolar epithelial cells, brain cells, COVID patients with cognitive impairment, often referred
Table 1. Hypothetical mechanisms underlying long COVID‑associated neurological sequelae

Proposed consequences of COVID‑19 Potential contribution to long COVID‑associated References
infection neurological symptoms
Persistent virus or antigen reservoir Ongoing immune or inflammatory activation 17,29
Damage in CNS and other associated regions Reduced brain volume, structural abnormalities, and tissue 17,29
damage in areas such as the anterior cingulate cortex,
orbitofrontal cortex, insula, amygdala, ventral striatum,
hippocampus, and parahippocampal gyrus, which are
connected to the primary olfactory cortex
Changes in inflammatory response, cytokine Downstream effects from neuroinflammation to neuronal 11,17
levels, and T-cell profile damage
Vascular endothelial activation or dysfunction Impact on platelet activation, clotting, microclots, and gas 17
exchange
Mitochondrial dysfunction and proteostasis Overproduction of ROS and RNS, deregulation of UPR 9
Autoimmunity Potential role of autoimmune autoantibodies or T cells 17
causing endothelial activation, postural orthostatic
tachycardic syndrome, myocarditis, and neuroinflammation
Microbial dysbiosis Altered metabolomic programming affecting immune 9
response
Abbreviations: COVID-19: Coronavirus disease-2019; CNS: Central nervous system; ROS: Reactive oxygen species; RNS: Reactive nitrogen species;
UPR: Unfolded protein response.

Volume 3 Issue 4 (2024) 5 doi: 10.36922/an.4267