Protein Expression Profile of ACE2 in the Normal and COVID-19-Affected Human Brain

Abstract

SARS-coronavirus 2 (SARS-CoV-2) that caused the coronavirus disease 2019 (COVID-19) pandemic has posed to be a global challenge. An increasing number of neurological symptoms have been linked to the COVID-19 disease, but the underlying mechanisms of such symptoms and which patients could be at risk are not yet established. The suggested key receptor for host cell entry is angiotensin I converting enzyme 2 (ACE2). Previous studies on limited tissue material have shown no or low protein expression of ACE2 in the normal brain. Here, we used stringently validated antibodies and immunohistochemistry to examine the protein expression of ACE2 in all major regions of the normal brain. The expression pattern was compared with the COVID-19-affected brain of patients with a varying degree of neurological symptoms. In the normal brain, the expression was restricted to the choroid plexus and ependymal cells with no expression in any other brain cell types. Interestingly, in the COVID-19-affected brain, an upregulation of ACE2 was observed in endothelial cells of certain patients, most prominently in the white matter and with the highest expression observed in the patient with the most severe neurological symptoms. The data shows differential expression of ACE2 in the diseased brain and highlights the need to further study the role of endothelial cells in COVID-19 disease in relation to neurological symptoms.

ACE2 Receptor and TMPRSS2 Protein Expression Patterns in the Human Brainstem Reveal Anatomical Regions Potentially Vulnerable to SARS-CoV-2 Infection

“…Overall, while the expression of ACE2R and TMPRSS2 was mostly moderate in the human brainstem, immunoreactive neurons and glial cells were clearly detected in several anatomical loci. On the other hand, Lindskog et al recently evaluated the expression of ACE2R in the human brain but did not detect significant neuronal or glial immunoreactivity in the brainstem. Various aspects need to be taken into account to explain differences in our studies: cohort size, post-mortem interval, differences in fixation, antigen retrieval methods, and antibodies employed.…”

“…This finding is also correlated with higher morbidity and mortality rates from COVID-19 in the elderly population . However, despite the relevant role played by these proteins in both health and disease, studies on ACE2R distribution and expression throughout the human CNS are limited, − and very little information is available concerning the brainstem, despite prominent involvement of this structure in COVID-19; in particular, Hill et al revealed prominent ACE2R expression at the level of the pons by means of ELISA analysis; Lukiw et al also detected high levels of ACE2R expression in the pons and medulla oblongata in human subjects. Conversely, Lindskog et al performed immunohistochemical analyses on COVID-19 and normal brain samples but did not identify ACE2R expression in brainstem neurons, with the choroid plexus representing the most prominent site of immunoreactivity.…”

Mechanisms of gastrointestinal barrier dysfunction in COVID-19 patients

“…In addition, lipopolysaccharide (LPS) is recognized by Toll-like receptors, which transduce signals that stimulate release of inflammatory cytokines[ 53 - 55 ]. ACE2 is expressed in certain regions of the human brain as well as in neurons and SARS-CoV-2 can directly damage these target organs[ 56 ]. After SARS-CoV-2 infection, impairment of the gastrointestinal barrier causes leaky gut and increased translocation of bacterial metabolic components and toxins into the bloodstream, which activates the immune response and leads to systemic inflammation[ 57 - 59 ].…”

Exploring the Role of ACE2 as a Connecting Link between COVID-19 and Parkinson’s Disease

“…Given the key role of ACE2 in SARS-CoV-2 cell invasion, the AD-related alterations in ACE2 expression in various brain areas may affect the susceptibility of these regions to SARS-CoV-2 infection. Furthermore, ACE2 expression is increased in endothelial cells of the white matter of COVID-19 patients, and higher ACE2 levels were correlated with increased severity of neurological symptoms [ 138 ]. In this regard, it would be interesting to investigate the expression of the ACE2 protein in specific PD-related brain regions and its relationship to SARS-CoV-2 infection.…”