Higher Angiotensin I Converting Enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer's disease. (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of death in the elderly. Cognitive decline due to Alzheimer's disease (AD) is frequent in the geriatric population disproportionately affected by the COVID-19 pandemic. Interestingly, central nervous system (CNS) manifestations have been reported in SARS-CoV-2-infected patients. In this study, we investigated the levels of Angiotensin I Converting Enzyme 2 (ACE2), the main entry receptor of SARS-COV-2 in cells, in postmortem parietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein and mRNA were found in individuals with a neuropathological diagnosis of AD compared to age-matched healthy control subjects. Brain levels of soluble ACE2 were inversely associated with cognitive scores (p = 0.02), markers of pericytes (PDGFR{beta}, p=0.02 and ANPEP, p = 0.007) and caveolin1 (p = 0.03), but positively correlated with soluble amyloid-{beta} peptides (A{beta}) concentrations (p = 0.01) and insoluble phospho-tau (S396/404, p = 0.002). No significant differences in ACE2 were observed in the 3xTgAD mouse model of tau and A{beta} neuropathology. Results from immunofluorescence and Western blots showed that ACE2 protein is mainly localized in neurons in the human brain but predominantly in microvessels in the mouse brain. The present data show that an AD diagnosis is associated with higher levels of soluble ACE2 in the human brain, which might contribute to a higher risk of CNS SARS-CoV-2 infection.

Higher ACE2 expression in the brains of individuals with Alzheimer’s disease

Background The emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a major cause of death, particularly in the elderly. The geriatric population in which cognitive decline due to Alzheimer’s disease (AD) is frequent is disproportionately affected by the pandemic. In addition, central nervous system (CNS) manifestations have been reported in a significant subset of SARS‐CoV‐2 infected patients. Method Since the principal entry receptor utilized by SARS‐COV‐2 is Angiotensin‐Converting Enzyme 2 (ACE2), we examined whether ACE2 protein and mRNA levels were altered postmortem in parietal cortex samples from two different AD cohorts, totalling 142 cases. Results Both immunoblot and RT‐qPCR analysis revealed higher concentrations of ACE2 protein and mRNA in persons with a neuropathological diagnosis of AD, compared to age‐matched controls. Brain levels of ACE2 were inversely correlated with antemortem cognitive scores. We found that ACE2 protein was highly enriched in microvessels of mice compared to brain parenchyma, but not in humans. Detachment of ACE2 from brain cell membranes was strongly associated with pericytes loss. No significant change of ACE2 protein was detected in the parietal cortex from the 3xTg‐AD mouse model of AD neuropathology. Conclusion Our data suggest that cognitive impairment is associated with higher levels of ACE2 in the brain, which might contribute the higher risk of CNS SARS‐CoV‐2 infection in cognitively impaired individuals and AD patients.