Ubiquity of the SARS-CoV-2 receptor ACE2 and upregulation in limbic regions of Alzheimer’s disease brain

Abstract

The major route of entry for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) into human host cells is by means of the angiotensin-converting enzyme-2 (ACE2) transmembrane receptor. This zinc-containing carboxypeptidase and membrane-integral surface receptor is ubiquitous and widely expressed in multiple cell types. Hence SARS-CoV-2, an unusually large RNA virus that causes coronavirus disease 2019 has the remarkable capacity to invade many different types of human host cells simultaneously. Although COVID-19 is generally considered to be primarily an acute respiratory disease SARS-CoV-2 also targets specific anatomical regions of the central nervous system (CNS).In the normal CNS the highest ACE2 levels of expression are found within the medullary respiratory centers of the brainstem and this, in part, may explain the susceptibility of numerous COVID-19 patients to severe respiratory distress. About ~35% of all COVID-19 patients experience neurological and neuropsychiatric symptoms, and a preexisting diagnosis of Alzheimer's disease (AD) predicts the highest risk of COVID-19 yet identified, with the highest mortality among elderly AD patients. In the current study of multiple anatomical regions of AD brains compared to age-, post-mortem interval-and gender-matched controls (n = 10 regions, n = 32 brains), ACE2 expression was found to be significantly up-regulated in AD in the occipital lobe, temporal lobe neocortex and hippocampal CA1. The temporal lobe and hippocampus of the brain are also targeted by the inflammatory neuropathology that accompanies AD, suggesting a significant mechanistic overlap between COVID-19 and AD, strongly centered on invasion by the neurotropic SARS-CoV-2 virus via the increased presence of ACE2 receptors in limbic regions of the AD-affected brain.

microRNA, the Innate-Immune System and SARS-CoV-2

“…The SARS-CoV-2 viral lipoprotein envelope is decorated with ‘E’, ‘M’, and ‘S’ proteins - the ‘S’ protein is a class 1 homo-trimeric viral fusion protein possessing distinctive ‘head’ and ‘stalk’ domains essential for host cell entry via the angiotensin converting enzyme 2 (ACE2) receptor (see below; Ke et al., 2020 ; Raghuvamsi et al., 2021 ; Lukiw, 2021 ). As discussed further below, using various miRNA-mRNA and miRNA-ssvRNA search algorithms, ‘ in silico ’ analysis and experimental validation, multiple naturally occurring human host miRNAs have been both predicted and verified to target several of these key SARS-CoV-2 genomic protein-encoding regions ( Arisan et al., 2020 ; Finkel et al., 2021 ; Zhao et al., 2021 ). This Perspectives paper will address some of the most current findings and emerging concepts in this fascinating research area of potential miRNA contribution to human innate-immunity with special reference to natural host miRNAs, SARS-CoV-2, and the current COVID-19 pandemic.…”

“…The ACE2 receptor is a zinc-containing carboxypeptidase membrane-integral cell-surface receptor widely expressed in multiple cell types that is uniquely recognized by the SARS-CoV-2 virus ‘S’ glycoprotein for initial human host cell entry ( Ke et al., 2020 ; Pierce et al., 2020 ; Hill et al., 2021 ; Lukiw, 2021 ; Raghuvamsi et al., 2021 ; Zhao et al., 2021 ). As the major SARS-CoV-2 cell surface-exposed transmembrane glycoprotein receptor ACE2 displays a significant variability in abundance on multiple human cell types and this may not only add another degree of variability for SARS-CoV-2 cellular invasion but also modulates SARS-CoV-2 exposure to the variable miRNA abundance and speciation in different human cell types ( Ke et al., 2020 ; Hill et al., 2021 ; Zhao et al., 2021 ).…”

“…The ACE2 receptor is a zinc-containing carboxypeptidase membrane-integral cell-surface receptor widely expressed in multiple cell types that is uniquely recognized by the SARS-CoV-2 virus ‘S’ glycoprotein for initial human host cell entry ( Ke et al., 2020 ; Pierce et al., 2020 ; Hill et al., 2021 ; Lukiw, 2021 ; Raghuvamsi et al., 2021 ; Zhao et al., 2021 ). As the major SARS-CoV-2 cell surface-exposed transmembrane glycoprotein receptor ACE2 displays a significant variability in abundance on multiple human cell types and this may not only add another degree of variability for SARS-CoV-2 cellular invasion but also modulates SARS-CoV-2 exposure to the variable miRNA abundance and speciation in different human cell types ( Ke et al., 2020 ; Hill et al., 2021 ; Zhao et al., 2021 ). In fact, the ACE2 receptor, the gateway for SARS-CoV-2 entry into the host cell, has a remarkable ubiquity, and has been detected on the surface of every human cell type so far analyzed with the exception of the erythrocyte, thus making it among the most prevalent receptor subtype encountered in all of human physiology ( Hill et al., 2021 ; Jones et al., 2021 ; Zhao et al., 2021 ).…”

“…As the major SARS-CoV-2 cell surface-exposed transmembrane glycoprotein receptor ACE2 displays a significant variability in abundance on multiple human cell types and this may not only add another degree of variability for SARS-CoV-2 cellular invasion but also modulates SARS-CoV-2 exposure to the variable miRNA abundance and speciation in different human cell types ( Ke et al., 2020 ; Hill et al., 2021 ; Zhao et al., 2021 ). In fact, the ACE2 receptor, the gateway for SARS-CoV-2 entry into the host cell, has a remarkable ubiquity, and has been detected on the surface of every human cell type so far analyzed with the exception of the erythrocyte, thus making it among the most prevalent receptor subtype encountered in all of human physiology ( Hill et al., 2021 ; Jones et al., 2021 ; Zhao et al., 2021 ). Interestingly, the ACE2 receptor mRNA is itself targeted by multiple natural host miRNAs and this may also have a bearing on the availability of ACE2 receptor abundance on multiple cell and tissue types in different human hosts – an observation that may be useful in the personalized diagnosis of COVID-19 ( Wicik et al., 2020 ).…”

Does SARS-CoV-2 affect neurodegenerative disorders? TLR2, a potential receptor for SARS-CoV-2 in the CNS

“…However, Lim and colleagues showed an increased level of ACE2 in the brain tissue of AD patients 65 . Zhao and colleagues found that ACE2 expression was upregulated in the occipital and temporal lobes and the hippocampal CA1 region in AD patients compared to healthy controls 66 . Therefore, further studies are required to evaluate the role of ACE2 in AD pathogenesis.…”