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Advanced Neurology SARS-CoV-2 mechanisms of neurological impact

permeability appears to persist independently of age, 6. The role of astrocytes and microglia in
emphasizing its potential role in chronic neurological COVID-19-associated neuroinflammation
symptoms. Structural changes, such as reduced gray and CI
matter volume and increased cerebrospinal fluid, have
also been correlated with BBB dysfunction in long COVID 6.1. Astrocytes: Mediators of neuroinflammation
patients. 121 and CI in COVID-19
Increased levels of several inflammatory biomarkers, Astrocytes are key players in the neuroinflammatory
including IL-8, glial fibrillary acidic protein (GFAP), and response to COVID-19. Studies have shown that astrocytes
transforming growth factor-beta (TGF-β), have been in COVID-19 patients exhibit reduced process complexity,
observed in patients with long COVID, particularly shortened process lengths, and enlarged cell bodies. 101,134,135
among those experiencing brain fog. 124,125 TGF-β, known Furthermore, clusters of astrocytes associated with
for its role in BBB disruption and structural brain changes, COVID-19 demonstrated upregulation of inflammatory
has also been implicated in chronic fatigue syndrome, a and astrogliosis-related genes, such as interferon-induced
condition with clinical similarities to long COVID. 126,127 In transmembrane protein 3 and GFAP. These astrocytes
addition, GFAP, typically associated with cerebrovascular also secrete neurotoxic factors like chitinase 3-like 1,
damage, is elevated in individuals with long COVID and contributing to neuronal death, which parallels astrocytic
related neurological impairments. 124,128 involvement in AD. 136,137
Animal models and postmortem studies provide Activated microglia can induce the formation of
further evidence of BBB compromise in COVID-19, neurotoxic A1 astrocytes by secreting cytokines such as
revealing fibrinogen leakage and coagulation dysregulation IL-1α, TNF-α, and complement component 1q (C1q).
in brain tissue. 91,119 Mouse models, in particular, displayed These A1 astrocytes promote neuronal and oligodendrocyte
abnormalities such as “string vessels,” indicative of blood death, further contributing to neurodegeneration in
vessel pathology. Research consistently demonstrates conditions like AD. On the other hand, astrocytes also
129
that inflammation and coagulation dysregulation are participate in amyloid-beta (Aβ) clearance by facilitating
pivotal factors in the pathophysiology of disease in patients its transport across the BBB, which may help prevent
recovering from COVID-19. 130 its accumulation (Table 4). 138-142 However, the exact
The long-term neurological effects may be partly mechanisms by which astrocytes and microglia interact
attributable to the SARS-CoV-2 spike protein itself. Studies during COVID-19-induced CI remain unclear and warrant
have shown that the spike protein can induce coagulation further investigation.
dysregulation and neurodegeneration when injected into Astrocytes play essential roles in neurotransmitter
the brain, and it has been detected in immune cells up recycling, maintaining synaptic transmission, and regulating
to 15 months post-infection (Table 3). 131,132 Its persistent neuronal excitability. 143,144 They modulate glutamate levels
presence may underlie symptoms of long COVID, such to prevent excitotoxicity. In SARS-CoV-2-infected mixed
as brain fog. In vitro studies also indicate that spike glial cultures, a significant reduction in L-glutamine levels
protein exposure activates brain endothelial cells, leading has been observed, impairing neuronal metabolism and
to increased inflammatory cytokine production and synaptic function. Inhibition of L-glutamine reduced
elevated expression of cell adhesion molecules, which may viral replication and the inflammatory response, further
exacerbate BBB dysfunction. 131,133 disrupting neuronal homeostasis. In addition, SARS-
134
Growing evidence underscores the crucial role of BBB CoV-2 infection in astrocytes led to metabolic changes,
integrity in the neurological manifestations of SARS- such as reduced lactate levels, depriving neurons of crucial
CoV-2 infection, particularly with respect to CIs like brain energy sources and contributing to CI and neuronal death.
121
fog observed in long COVID. The persistent disruption
of the BBB, driven by systemic inflammation and 6.2. Microglia: Dual roles in neuroinflammation and
coagulation dysregulation, presents a significant challenge cognitive decline
in understanding and treating the long-term effects of Microglia, the brain’s resident immune cells, play a complex
COVID-19. Future research should prioritize longitudinal role in neurodegenerative diseases such as AD, exhibiting
studies to better elucidate the mechanisms contributing both protective and harmful functions. 145,146 While
to BBB dysfunction and to develop therapeutic strategies moderate microglial activation is beneficial for clearing Aβ
aimed at preserving or restoring BBB integrity, which in the brain, overstimulation by Aβ or amyloid precursor
could alleviate chronic neurological symptoms in post- protein (APP) can trigger excessive inflammatory
COVID patients. responses, potentially accelerating neurodegeneration

Volume 4 Issue 2 (2025) 20 doi: 10.36922/an.4909