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

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

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

ACE2 and TMPRSS2 Expression in the ENS and Choroid Plexus

The expression of angiotensin-converting enzyme 2 (ACE2) in various structures of the central nervous system (CNS), including neurons, neuroglial cells, and the blood-brain barrier (BBB), provides potential pathways for SARS-CoV-2 neuroinvasion. Because the virus uses the ACE2 receptor to enter host cells, the presence of ACE2 in these tissues increases the risk of direct infection and subsequent neurological complications.

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COVID-19 patients have shown symptoms of direct and indirect neurological effects, from changes in taste and smell, to immunologic factors in cerebral spinal fluid (CSF).  It is unknown whether these phenomena are the result of neurological damage, of SARS-CoV-2 infection, and/or of indirect effects of the immune response. Furthermore, studies in mice have shown that neurons are susceptible to infection, suggesting that cells of the CNS may contribute to the deteriorating breathing and respiratory function of COVID-19 patients. The image below is an early hypothesized mechanism of viral entry through nasal and oral mucosa cells, though there is not yet any evidence to support this hypothesis.

Effects of COVID-19 on the Central Nervous System

Three primary observations have been made about ACE2 and its relation to SARS/COVID-19:

- ACE2 acts as a functional receptor for SARS-CoV-2 to enter host cells
- Increased ACE2 expression may elevate the risk of a SARS-CoV-2 infection as well as the development of COVID-19
- Reduced ACE2 expression may lead to acute respiratory distress syndrome

SARS‐CoV‐2 may be able to infect other tissues that express ACE2 using viral RNA that circulates in the blood.  

ACE2 in the Pathogenesis of COVID-19

ACE2 expression was quantified in 21 regions of the human brain using multiple tissue expression (MTE) arrays (*p < 0.01 (ANOVA); error bars represent one standard deviation of the mean).  The highest expression was found in the pons, amygdala, and the medulla oblongata.  The pons and medulla oblongata are notably known to control breathing and respiration. 

ACE2 Expression in the Human Brain

Many of the known coronaviruses are neurotropic, meaning they are able to infect neuron cells.  If these observed trends carry over to SARS-CoV-2, they could help to elucidate how the CNS is affected by COVID-19.  Some of the key observations include:

- human coronavirus OC43 was shown to transmit itself to different neurons via axons in mice
- neuronal ACE2 expression in mice was found to be in different pre-autonomic regions of the brain which could explain why infected COVID-19 patients with dangerously low blood oxygen levels don't gasp for air
- SARS-CoV was found to infect regions of the brain that deal with cardiopulmonary regulation in human ACE2 knock-in mice
- SARS-CoV patient autopsies showed that the virus affected neurons more than any other kind of cell

Trends in Other Coronaviruses Affecting the CNS
 Relevant to COVID-19

- Autoimmune Response Contribution to Neurological Symptoms.
- Neuro-Immune Cellular Interactions from SARS-CoV-2 Infection.

Indirect/Downstream effects of SARS-CoV-2 on the CNS.

Even in the absence of typical respiratory symptoms such as fever, cough, and shortness of breath, various patients diagnosed with COVID-19 have presented neurological symptoms, such as:

- acute cerebrovascular diseases

- impaired consciousness

-  skeletal muscle injury

- encephalopathy (symptoms: ischemic stroke)

- loss of smell (anosmia) and taste (ageusia)

- stroke

- cranial nerve deficits

- delirium

- meningitis

- paralysis

- seizures

- neuroinflammatory syndromes

- high pressure CSF

- muscle stiffness

The list below includes less-common neurological symptoms of COVID-19:
- Guillain–Barré syndrome (GBS)
- Multisystem Inflammatory Syndrome in Children (MIS-C)

Neurological symptoms Presented in COVID-19 Patients

- Brain degeneration

- Cognitive decline

- Mental disorders


Expected Long-Term Outcomes of Acute SARS-Cov2 Infection on CNS

- Hypothesized Mechanisms for SARS-CoV-2 Direct Invasion of the CNS
- Controversy: Is SARS-CoV-2 "Neuroinvasive"?

Direct Effects of SARS-CoV-2 on the CNS.

ACE2 and its Implications in SARS-CoV-2 Infection of the CNS

SARS-CoV-2 relies on its spike (S) protein to bind to cellular receptors to enter host cells. SARS-S, the SARS spike protein, uses ACE2 as an entry receptor into cells. Then the virus utilizes the serine protease TMPRSS2 found within the cell to enhance entry and prime future S proteins. SARS‐CoV‐2 is thought to be more transmissible than others CoVs because its S proteins have a greater affinity for ACE2.

ACE2 as a Receptor for SARS-CoV-2

ACE2 is known to be expressed in a variety of different tissues, including:

- Heart, kidneys, gastrointestinal (GI) tract, lungs, brain, testes, bladder, adipose tissue, vascular system, cholangiocytes (epithelial cells of the oral and nasal mucosa)

ACE2 expression may explain the SARS-CoV-2 organ localization.

Expression of ACE2 in Tissue and COVID-19

Some believe that the body may initiate an autoimmune response when SARS-CoV-2 is attached to an ACE2 receptor.  The body may consider this complex antigenic, meaning it produces antibodies.  However, these antibodies would target both the virus and ACE2.  This theory is substantiated by:

- the patterns of lung damage in patients with Pulmonary Hypertension secondary to Scleroderma, which is hallmarked by high levels of anti-ACE2 antibodies
- the severity of COVID-19 immune responses in those with cardiovascular disease and hypertension, who would be likely to have increased levels of ACE2 receptors in their blood serum

Measuring ACE2 levels in serum could be a way of predicting at-risk groups for ARDS (acute respiratory distress syndrome) and other hyperimmune responses.  

Autoimmunity to ACE2 Theory in the Pathogenesis of COVID-19

COVID-19 results in the down-regulation of ACE2 receptors by the virus binding to transcription factors at ACE2 regulatory regions on the gene.  This results in increased concentrations of Ang II, which would normally be converted to Ang 1-7 by ACE2.  This may contribute to the hyper-inflammation seen in COVID-19 patients.  

SARS-CoV-2 Down-Regulates ACE2 Receptors

- Increased Concentrations of Circulating ACE2 is Associated with Mild COVID-19 Symptoms 
- Circulating ACE2 expression compared to circulating ACE

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