- Increasing data suggest that ACE2 is not appreciably expressed in neurons in the brain at either the RNA or protein level. 
- scSeq analysis of human prefrontal cortex and hippocampus failed to identify any ACE2- expressing cells 
- multiple immunostaining studies have demonstrated ACE2 expression in brain vasculature but not in neurons or glia 


Smith College

The points below list major concerns surrounding speculation of SARS-CoV-2 neuroinvasion:
- Assessing the ability for SARS-CoV-2 to infect human neurons (in the bulb or elsewhere) will ultimately require detailed analysis of autopsy tissue, studies of which do not yet exist.
- Many of the observed neurological consequences of COVID-19 (like altered consciousness and stroke) can in principle be explained by a primary asculopathy and hypercoagulability or by a secondary deficit in brain perfusion caused by elevated cytokines, rather than by direct viral damage


Controversy: Is SARS-CoV-2 ‘‘Neuroinvasive’’? 


1. Entry through the naval cavity: because intranasal drug delivery bypasses the blood brain barrier to delivery therapeutic agents directly to the CNS, it is thought that SARS-CoV-2 can likewise infect the brain via olfactory nerves.
  
2. Entry through the lungs: previous speculation that SARS-CoV could infect the , brainstem via chemoreceptors and mechanoreceptors in the respiratory system lend possibility for a neurotropic mechanism for SARS-CoV-2.

These hypotheses have yet to be validated.  
Figure below shows coronavirus infection mechanisms (Wu et. al).

Hypothesized Mechanisms for SARS-CoV-2 Direct Invasion of the CNS 

Cooper, K. W., Brann, D. H., Farruggia, M. C., Bhutani, S., Pellegrino, R., Tsukahara, T., ... & Albers, M. W. (2020). COVID-19 and the chemical senses: supporting players take center stage. Neuron.
https://doi.org/10.1016/j.neuron.2020.06.032
https://www.sciencedirect.com/science/article/pii/S0896627320304864

COVID-19 and the Chemical Senses: Supporting Players Take Center Stage

Support Against SARS-CoV-2 Direct Invasion of Neurons and Glial Cells

The points below describe early belief in the possibility that SARS-CoV-2 can directly infect neurons or glia:
- there is low-level expression of ACE2 in human middle temporal gyrus, posterior cingulate cortex, astrocytes, and oligodendrocytes as well as in artificial stem-cell derived neurons
However, these conclusions are drawn upon studies assessing the presence or absence of ACE2 expression, without any functonal data for support.

Support for SARS-CoV-2 Direct Invasion of Neurons and Glial Cells

- K18-hACE2 mice brain tissue shows no viral infection in olfactory tissue

Reports Supporting SARS-CoV-2 Direct CNS Invasion Through the Lungs

- Potential neuroinvasive pathways of SARS-CoV-2: Deciphering the spectrum of neurological deficit seen in coronavirus disease-2019 (COVID-19)
- SARS-CoV-2 entry through the blood brain barrier (BBB)

Potential neuroinvasive pathways of SARS-CoV-2

Viral RNA and protein found in olfactory mucosa and CNS. SARS-CoV-2 suggested to exploit the neural–mucosal interface as a port of entry into the CNS. 

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