Epistatic impact of APOE and ACE2 genetic variants on SARS-CoV-2 and RAS dependent blood-brain barrier dysregulation.




0009-0008-2702-1983 (Tate, Amanda)
0000-0001-6857-0286 (Barber, Robert)
0000-0003-3248-0355 (Jones, Harlan)
0000-0002-9324-2687 (Phillips, Nicole)

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Coronavirus disease 2019 (COVID-19) is associated with respiratory and neurodegenerative symptoms, creating a need to understand the additional impact the pandemic might have on neurodegeneration and risk for neurodegenerative diseases, such as Alzheimer’s disease (AD) in aging populations post 2020. The blood-brain barrier (BBB) is an important interface that connects the periphery to the brain through the vasculature. When this protective barrier becomes dysregulated, the brain is vulnerable to infection, neuroinflammation, and cellular stress, which over time can lead to neurodegeneration and cognitive decline. The renin-angiotensin system (RAS) is an important regulator of vasculature via the activity of the hormone angiotensin II (Ang II). As a mediator of vasoconstrictive, oxidation, and inflammatory responses, its prolonged activity can be damaging and promote neurodegeneration at the BBB. Angiotensin-converting enzyme 2 (ACE2) is highly expressed in endothelial cells which cleaves Ang II into less harmful fragments to offset these potentially toxic effects. Genetic variants of ACE2 are increasingly considered risk factors for the development of vascular disorders (e.g. hypertension) due to their role in RAS-mediated dysregulation of body vasculature. Recent genetic studies have identified a relationship between genetic variants for ACE2, an obligate receptor for the severe acute respiratory syndrome coronavirus 2 (SCoV2), and increased risk and or/severity of COVID-19. Alzheimer’s disease (AD) is the greatest neurological risk among aging individuals and can be caused by both environmental & genetic risk factors. The strongest genetic risk factor for AD is variants in the apolipoprotein E gene (APOE), with the ɛ4 allele being associated with increased levels of amyloid β (Aβ), Tau proteins (p-Tau), neuroinflammation, and BBB permeability. A recent study by Wang et al also suggests a correlation between APOE ɛ4 and increased severity of COVID-19, suggesting some interplay between APOE and host factors related to SCoV2 infection. Furthermore, both ACE2 and APOE genetic variants disproportionately impact minority populations, highlighting a need to understand the health disparity of AD and COVID-19 risk across demographic groups. We hypothesize gene interactions (epistatic interactions) between genetic variants in ACE2 and APOE may exacerbate RAS-mediated BBB dysregulation, leading to increased AD phenotypes and SCoV2 neurological dysregulation. To address this hypothesis, we will create endothelial cells, astrocytes, and neurons containing APOE and ACE2 genetic variants of interest. These epistatic cells will be assessed for expression and functional changes related to BBB integrity. Using Ang II treatments and SCoV2 pseudo-virus models, we will assess the impact of COVID-19 and RAS on BBB integrity and functions. This study will help us understand the mechanisms and interplay of genetic risks for AD and COVID-19 related to RAS-mediated BBB dysregulation, potentially highlighting comorbidities among the aging population. By focusing on ACE2 variants disproportionately found in minority populations, we will provide knowledge surrounding two co-morbidities for neurodegeneration and elevate those at the highest risk for developing AD and/or COVID-19. Funding: This work is supported by the Neurobiology of Aging and Alzheimer’s Disease T32 Training Fellowship, and the IMSD Fellowship, Grant # 5 R25 GM125587-05 from the National Institutes of General Medical Sciences (NIGMS).