key: cord-0734264-1b774vki
authors: Lim, Key-Hwan; Yang, Sumin; Kim, Sung-Hyun; Joo, Jae-Yeol
title: Elevation of ACE2 as a SARS-CoV-2 entry receptor gene expression in Alzheimer's disease
date: 2020-06-30
journal: J Infect
DOI: 10.1016/j.jinf.2020.06.072
sha: 2b3b394a8e05b2c123bd98cb15d14b716d1eed39
doc_id: 734264
cord_uid: 1b774vki

nan

We read with a recent study by Liu and colleagues, published in the Journal of Infection, described the mortality of elderly patients with Covid-19 compared to young and middle-age patients. 1 In addition, we also read an interest article by Fu and colleagues in this journal, the SARS-CoV-2 pandemic that showed high mortality in older adults who have chronic comorbidities such as chronic obstructive pulmonary disease (COPD). 2 Considering the high mortality rate and pandemic status of COVID-19, development of effective therapeutics is an urgent issue that requires the identification of quality pathogen. Genomic characterization recently revealed that angiotensin-converting enzyme 2 (ACE2) is a SARS-CoV-2 binding protein for cell entry, and control of ACE2 is a potential therapeutic target to reduce SARS-CoV-2 transmission. 3 Thus, there is an urgent need for studies of genomic expression of Ace2 gene in elderly COVID-19 patients. The hope is that such studies will allow researchers to decrease the mortality rate and prevent new SARS-CoV-2 infections.

A main risk factor for the development of neurodegenerative diseases (NDs) is aging, Alzheimer's disease (AD) is the most common ND in older adults. 4 The main cause of AD is the aggregation of A β peptide in brain tissue; several related symptoms, such as hippocampal sclerosis, are frequently detected. 5 Moreover, a recent study suggested that AD patients who have comorbidities such as COPD showed increased cognitive decline. 6 Given that AD patients have particularly susceptible respiratory systems, we hypothesized that high ACE2 expression may be related to higher mortality in AD patients. We thus queried RNA-seq data and performed a genome-wide association study (GWAS) for Ace genes in an AD model ( Fig. 1 A) . Expression analysis of the increase in Ace genes in the AD mouse model showed dominant expression of the Ace2 gene in brain tissue ( Fig. 1 B) . However, unlike Ace2, Ace1 gene expression did not differ in healthy vs. diseased brain tissue ( Fig. 1 B) . We also analyzed Ace2 gene expression levels in blood and found no significant differences ( Fig. 1 B) . Ace1 gene expression showed a slightly decreased tendency in AD brain tissue; on the other hand, we observed that Ace1 gene expression was significantly increased in blood ( Fig. 1 B) . This means that Ace1 gene may be a specific biomarker for AD diagnosis. Having observed changes in Ace gene expression levels in AD model brain and blood, we next analyzed human Ace gene expression profiles in the brain tissue and peripheral blood mononuclear cells (PBMCs) of human AD patients. Gene difference analysis showed that Ace2 gene expression levels gradually elevated in incipient (135%), moderate (148%), and severe patients (164%) groups vs. healthy groups, however Ace1 gene expression levels decreased by 32% in incipient patients, and then return to normal levels in moderate and severe patients groups (111% and 116%, respectively) ( Fig. 1 C) . On the other hand, Ace1 gene was expressed at a level of 39% and Ace2 gene was expressed at a level of 69% compared to the normal groups. ( Fig. 1 D) . These analyzes strongly indicate that Ace2 gene expression is elevated in AD brain tissue, which may be a risk factor for Covid-19 transmission in AD patients. Advancements in Covid-19 host genomics research are currently required for development of medicine or therapeutics. 7 Here, we report on genetic risk factors for transmission of SARS-CoV-2 in AD patients using GWAS. Emerging analyses may link these findings to prevention or therapeutics for SARS-CoV2. We found that expression of the Ace2 gene, which codes for a SARS-Cov-2-binding protein, was increased in AD patient brain. Interestingly, ACE inhibitors have recently been suggested as treatments for NDs. 8 Therefore, ACE inhibitors may treat both NDs and Covid-19. Collectively, our results suggest that high ACE2 expression may be a risk factor for Covid-19 transmission in AD patients. Careful diagnosis and healthcare provisions are needed to address this issue therapeutically.

All financial and non-financial competing interests. Letter to the Editor / Journal of Infection 81 (2020) e33-e34 Fig. 1 . Ace2 gene expression profiling in AD patient brain. ( A ) Gene expression is quantified by total RNA-seq. Extracted total RNAs were synthesized to cDNA using random primers. Gene expression profiling was based on Agilent GeneSpring analysis; image was generated by the FASTQ illumine package bcl2faseq. Single-or paired-end reads were calculated from next generation sequencing (NGS). ( B ) Visualization of Ace1 and Ace2 gene expression in the UCSC genome browser. Representative UCSC genome browser tracks of Ace1 and Ace2 are shown for cortex and whole blood. Total RNA-seq covered for whole Ace1 and Ace2 gene expression region and mapping each sequencing reads. Ace2 fragments per kb per million reads (FPKM) values are significantly increased in 5xFAD cortex. Ace1 FPKM values are increased in AD model blood. There was no significant change of Ace1 in 5xFAD cortex. Ace2 showed very small amount of gene expression both WT and 5xFAD. The FPKM values for each gene were calculated with the Cufflinks package. ( C ) Analysis of Ace1 and Ace2 gene expression profile from human brain microarray dataset in AD patients. Gene expression analysis in hippocampus showed that Ace2 gene expression levels are elevated in the severe patient group compared to healthy group (135%, 148%, 164%, respectively). On the other hand, Ace1 gene expression levels decreased by 32% in incipient patients, and then return to normal levels in moderate and severe patient groups (111% and 116%, respectively). Control group n = 9, incipient group n = 7, moderate group n = 8, severe group n = 7. ( D ) Analysis of Ace1 and Ace2 gene expression profile from human PBMCs microarray dataset in AD patients. Gene expression analysis result in human PBMCs showed that Ace1 gene was expressed at a level of 39% compared to the normal groups, whereas Ace2 gene was expressed at a level of 69% compared to the normal groups. Normal patients group n = 3, Mild patients group n = 3, Severe patients group n = 3. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Clinical features of COVID-19 in elderly patients: a comparison with young and middle-aged patients

Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and metaanalysis

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

The British Infection Association

Ageing as a risk factor for neurodegenerative disease

Alzheimer's disease. Nat Rev Dis Primers

Chronic obstructive pulmonary disease may complicate Alzheimer's disease: a comorbidity problem

COVID-19 outcomes and the human genome

We would like to thank Dr. S.-W.L. for assistance of bioinformatics analysis.

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jinf.2020.06.072 .