ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway

Background Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes. Methods A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression. Results ApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18–1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50–2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1–7. Conclusions ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin–angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.