- The presence of the COVID-19 virus in the general circulation understandably enables it to pass into the cerebral circulation  (Figure 1A−C)
- Movement of the blood within the microcirculation could be one of the factors that may facilitate the interaction of the COVID-19 virus spike protein with ACE2 expressed in the capillary endothelium. 
- The budding of the viral particles from the capillary endothelium and damage to the endothelial lining can favor viral access to the brain (Figure 1B) 


Interaction Between Tissue Expression of ACE2 Receptors and SARS-CoV-2 Circulation.


- Investigate the density of the expression levels of ACE2 in the CNS
- Mechanism of the infection at molecular level
- Figures included

Smith College

- Neuronal ACE2 Expression as a Risk Factor for COVID-19
- Neuronal ACE2 Internalization in COVID-19
- ACE2 Expression in BBB
- ACE2 Expression in neuroglial cells
- ACE2 Expression in the ENS and Choroid Plexas

ACE2 and its Implications in SARS-CoV2 infection of the CNS

ACE2 was found to be heavily expressed in the cell body of artificial, stem cell derived neurons, and less so in the axons and dendrites. Data from human brain tissue is yet to be collected, but these findings as well as other studies using mice brain tissue suggest that ACE2 expression in neurons could make them susceptible to SARS-CoV-2 infection.  

Neuronal ACE2 Expression as a Risk Factor for COVID-19

ACE2 is a surface bound enzyme, but when mice neuro-2A cells were exposed to Ang II and AT1R was activated, ACE2 was removed from the surface of the cell and degraded by lysosomes.  This may be a relevant mechanism related to SARS-CoV-2 cell entry.  

Neuronal ACE2 Internalization in COVID-19

SARS-CoV-2 virus exploits the ACE2 receptor to gain entry into the cells

- SARS-CoV-2 may directly infect neurons via ACE2 protein on the surface of neurons. 
- Cytokines secreted from infected neurons damage nearby neurons and glial cells 


SARS-CoV-2 may directly infect neurons via ACE2 protein: possible mechanisms in figure

- SARS-CoV-2 may enter the blood vessels through mucosa and infected lungs: binds to ACE2 expressed in endothelial cells, disrupting the blood-brain barrier. - This may cause cerebral edema and intracranial hypertension. 


SARS-CoV-2 may enter BBB and affect CNS

- The ACE2 is expressed in both neurons and glia, particularly present in the brain stem and in the regions responsible for cardiovascular regulation
- SARS-CoV-1 was found in cerebrum not cerebellum may because by the distinct ratios between neurons and neuroglia(cerebrum has more glia cells)
- SARS-CoV-2 could  infect brain regions by triggering reactive astrogliosis and activation of microglia which leads to Neuroinflammation.
- Neuroinflammation together with prolonged hypoxia may promote neuropsychiatric developments and cognitive impairments both acute and chronic.

SARS-CoV-2 may infect CNS by targeting neuroglial cells  


- Histological Evidence for the Enteric Nervous System and the Choroid Plexus as Alternative Routes of Neuroinvasion by SARS-CoV2

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