Effects of apoE Isoform, Sex and Diet on Insulin Regulation in Brain

Project Summary: Severe acute respiratory syndrome-coronavirus (SARS-CoV-2) causes a world-wide pandemicinvolving a cytokine storm. Besides direct action at the lung and heart, SARS-CoV-2 has alsobeen shown to cross the blood-brain barrier (BBB), being recovered from cerebrospinal fluid(CSF) and brain tissue. Its ability to invade the brainstem and so affect central nervous system(CNS) control of breathing may contribute to its ability to induce respiratory failure. There areseveral reasons why Alzheimer's disease (AD) patients are at a special risk for COVID-19. Ageis a significant risk factor, where the elderly are more susceptible to COVID-19 by being morelikely to progress to severe disease, showing increased mortality and different clinical featuresthan young and middle-aged patients. The combination of COVID-19 and dementia, anotherpandemic currently present in our aging society, is being considered a "double hit" and raisesconcerns regarding dementia care during COVID-19. SARS-CoV-2 has 3 viral envelope proteins(S, E, and M) with the S being the protein that mediates attachment to the host cell, capable offusing to the angiotensin converting enzyme 2 receptor (ACE2R). Several lines of evidence linkACE and the apolipoprotein E (apoE) isoform, E4, another risk factor for developing AD. Whileworking directly with the SARS-CoV-2 virus is valuable, it requires working in an ABSL-3 levelfacility and substantially restricts studies with non-perfused tissues. SARS-CoV-2 recombinantvirus-like particles (VLPs) offer an attractive way to study the pathogenesis of SARS-CoV-2 inanimals, without the involvement of replicating viruses. In this application, using mice expressinghuman E3 or E4 under control of the mouse apoE promoter, we will investigate the mechanismsby which apoE isoform, sex, and age can affect SARS-CoV-2 VLP transport across the BBB andimpact on cognition.