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.
Circular RNAs (circRNAs) are highly expressed in the central nervous system and have been reported to be associated with neuropsychiatric diseases, but their potential role in major depressive disorder (MDD) remains unclear. Here, we demonstrated that there was a disorder of circRNAs in the blood of MDD patients. It has been preliminarily proved that hsa_circ_0002473, hsa_circ_0079651, hsa_circ_0137187, hsa_circ_0006010, and hsa_circ_0113010 were highly expressed in MDD patients and can be used as diagnostic markers for MDD. Bioinformatics analysis revealed that hsa_circ_0079651, hsa_circ_0137187, hsa_circ_0006010, and hsa_circ_0113010 may affect the neuroplasticity of MDD through the ceRNA mechanism.
GRK5 is a member of the G protein-coupled receptors (GPCRs) kinase family and is closely associated with Alzheimer's disease (AD). However, the biological function of GRK5 in the brain and the causal link between GRK5 deficiency and AD-like pathology is unknown. Here, we show that GRK5 is reduced in the AD mouse brain, and mice with reduced GRK5 in the hippocampus induce cognitive impairment. AD-like molecular pathology, such as significant neuronal damage and loss, enhanced tau proteins phosphorylation, and increased level of Aβ peptides in the hippocampus were also observed in the GRK5 deficiency mice. Mechanismly, GRK5 is located in microglia and plays an essential role in maintaining the morphology and function of microglia. CRK5 deficiency elicits microglial morphology change and pfo-inflammation-associated gene increase. In addition, transcriptional analysis of hippocampal tissues revealed that neuroactive ligand-receptor interactions and TNF signaling are striking changes in GRK5 deficiency mice, which have the same trend in the AD mouse. In conclusion, our results further confirm the vital role of GRK5 in maintaining normal cognitive function in mice. Provide a possible mechanism that GRK5 maintains the microglia homeostasis, and its loss may induce microglia function deficit and cause other AD-related molecular pathogenesis.
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