Written by - Chen Yanting

Editor-in-charge - Wang Sizhen

Editor — Binwei Yang

This article first describes COVID-19 as a respiratory disease, but there is growing evidence that SARS-CoV-2 is capable of invading the brains of people with COVID-19 and causing cognitive impairment

The olfactory nerve is mainly composed of olfactory receptor neurons that directly connect the nasal cavity and the central nervous system

Figure 1 Potential pathways for SARS-CoV-2 to enter the brain through the olfactory pathway

Clinical studies from 172 patients with COVID-19 have shown that the most common ocular symptom in patients with COVID-19 is conjunctivitis (23.

In addition, the possibility of ENTERal infection of SARS-CoV-2 in patients with COVID-19 is also of concern [8].

Examination of brain tissue in postmortem SARS-CoV-2 infected patients shows the presence of viral particles in brain capillaries, endothelial cells, pericytes, and neurons SARS-CoV-2 can invade brain tissue through BBB, possibly related to the presence of ACE2 receptors in endothelial cells [12-14] (Figure 3

(ii) SARS-CoV-2 infection triggers systemic inflammation and promotes BBB leakage In severe cases of COVID-19, SARS-CoV-2 infection can trigger systemic inflammation and cytokine storms
.

Using an in vitro BCEC model, the investigators found that elevated levels of pro-inflammatory factors after exposure to SARS-CoV-2 were closely related to
changes in TJ protein function and BBB destruction.

For example, cytokines such as IL-1, IL-1β, TNF-α, IL-6, and IL-12 can lead to degradation of TJ proteins (occludin, claudin-5, ZO proteins), resulting in impaired BBB permeability [17, 18].


Accompanied by inflammatory damage to BBB, the extravasation of immune cells through BBB increases, leading to an increase
in SARS-CoV-2 virus particles in the brain parenchyma, as well as pro-inflammatory cytokines.

Increased secretion of pro-inflammatory cytokines associated with COVID-19 impairs BBB integrity and accelerates the entry of SARS-CoV-2 into the brain parenchyma (Figure 3
).

In addition, virally infected white blood cells spread into the circulating bloodstream and, along with other immune cells, penetrate into the brain parenchyma, which may be another way
for the virus to enter the central nervous system.

White blood cells infected by neurotropophilic viruses can infiltrate the brain through the vasculature, meninges, and choroid plexus, a mechanism known as a "Trojan horse.
"

This evidence, combined with systemic inflammation and hypoxia conditions in COVID-19, suggests increased leukocyte infiltration through BBB during infection, which reinforces this pathway of SARS-CoV-2 invasion of nerves (Figure 3
).

Persistent systemic inflammation during COVID-19 infection is associated with cognitive decline and leads to persistent electroencephalogram (EEG) changes and hippocampal atrophy
.

Therefore, in the cognitive impairment associated with COVID-19, attention should be paid to the effects
of pro-inflammatory factors on the body.

SARS-CoV-2 infection causes pro-inflammatory cytokines to activate specific signaling cascades and increase BBB leakage by impairing the assembly and expression levels of TJ proteins, which in turn allows SARS-CoV-2, peripheral immune cells, and other molecules to enter the central nervous system, exacerbating brain damage
.
(3) SARS-CoV-2 infection leads to coagulation disorders, promotes TJ destruction and increases BBB permeability

Critically ill patients infected with SARS-CoV-2 usually present with elevated levels of D-dimer and severe thrombocytopenia, which may increase the incidence of
cerebrovascular events.

Coagulation data from 94 patients with confirmed COVID-19 were analyzed and the D-dimer, fibrin/fibrinogen degradation products, and fibrinogen water levels were significantly higher in all cases of SARS-CoV-2 infection than those in the healthy control group
.

Thrombin can increase BBB permeability
by activating Src kinase phosphorylation of MMP and TJ proteins and up-regulating VEGF.

In addition, vascular endothelial experiments have shown that fibrinogen can disrupt endothelial cell integrity by disrupting the TJ protein that binds to actin filaments
.

Increased actin formation may lead to cell stiffness, actin filament contraction, and widening of endothelial cell-cell connections, thereby disrupting endothelial cell integrity
.

These studies have shown that ischemia leads to an increase in endothelial permeability in which the thrombin, fibrinogen, and plasmin systems play a major role
.

In summary, coagulation system abnormalities caused by SARS-CoV-2 infection can increase the permeability of BBB by destroying the TJ protein and increase the entry of SARS-CoV-2 into the brain parenchyma (Figure 3
).

SARS-CoV-2 invades vascular endothelial cells to activate thrombosis and inflammatory cascade, leading to capillary occlusion
.

For example, in cognitively relevant brain regions (e.
g.
, hippocampus, temporal lobe), capillary-nourishing nerve cells are damaged by ischemia and hypoxia, thereby promoting vascular cognitive impairment
.

(4) Lung damage caused by SARS-CoV-2 leads to hypoxia and increases BBB permeability

Respiratory failure caused by lung damage can lead to severe hypoxia
of the brain.

Neurons rely on blood vessels to provide oxygen and nutrients
.

When brain tissue continues to be deprived of oxygen, it can eventually cause irreversible damage
to neurons.

Consistent with hypoxic brain injury, autopsies of COVID-19 have shown damage to neurons in the neocortex, hippocampus, and cerebellum
regions.

An in vitro BBB model was established by co-culturing mouse microvascular endothelial cells and astrocytes, and it was found that hypoxia reduced ZO protein expression and induced ZO protein phosphorylation
.

In addition, the researchers found through the bovine cerebral microvascular endothelial cell test that hypoxia led to a 2.
6-fold increase in actin rearrangement and a 2.
6-fold
increase in the cell permeability marker [^14C] sucrose.

These findings are consistent with previous reports of increased permeability of cerebral capillary endothelial cells 2 h to 48 h after hypoxia treatment [19, 20].


An increase in paracellular permeability of an oxygen-induced cerebral capillary endothelial cells may be associated with altered actin distribution and loss of TJ protein (Figure 3
).

Therefore, some patients with COVID-19 are expected to develop long-term neurocognitive sequelae after the acute illness resolves
.

In general, chronic cognitive sequelae of ischemia and hypoxia can range from mild attention and memory impairment to general cognitive decline and dementia or even coma
.

Summarize and look ahead to growing evidence that COVID-19 survivors suffer from neurological disorders
.

The brain is undoubtedly one
of the targets of COVID-19.

Although the exact pathophysiology of central nervous system infections is still being speculated, the mechanism of COVID-19 infection in the brain may be related to the high-density expression of ACE2 receptors in brain and other organ tissues and the entry of the virus into the brain through olfactory, trigeminal, optic, and vagus nerve pathways
.

Another route of blood transmission is also possible
.

The mechanism by which SARS-CoV-2 interacts with BBB may lead to neurological dysfunction
associated with SARS-CoV-2-induced COVID-19.

The effects of SARS-CoV-2 on brain tissue may lead to acute and long-term changes in the nervous system, or may exacerbate existing neurological disorders or symptoms
.

Thus, neurological invasion and BBB dysfunction may be potential pathways to facilitate the entry of SARS-CoV-2 into the central nervous system and may contribute to the cognitive impairment
observed during disease progression.

While it is too early to elucidate the long-term side effects of SARS-CoV-2 infection, there is growing evidence that SARS-CoV-2 may cause permanent sequelae of the central nervous system, including cognitive decline
.

However, whether SARS-CoV-2 can enter the brain and replicate in the brain parenchyma, and whether it has the ability to neuroincroach, remains to be explored
in the future.

In summary, with the advent of the post-epidemic era, the subsequent brain injury caused by SARS-CoV-2 will become a clinical symptom and social problem
that cannot be ignored.

Exploring the mechanisms and early interventions of cognitive dysfunction in patients with COVID-19 will improve the quality of life in
patients.
Original link: Https://doi.
org/10.
1186/s12974-022-02579-8
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