Severe acute respiratory syndrome-coronavirus (SARS-CoV-2) causes a world-wide pandemic involving a cytokine storm. Besides direct action at the lung and heart, SARS-CoV-2 has also been 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 are several reasons why Alzheimer?s disease (AD) patients are at a special risk for COVID-19. Age is a significant risk factor, where the elderly are more susceptible to COVID-19 by being more likely to progress to severe disease, showing increased mortality and different clinical features than young and middle-aged patients. The combination of COVID-19 and dementia, another pandemic currently present in our aging society, is being considered a ?double hit? and raises concerns 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 of fusing to the angiotensin converting enzyme 2 receptor (ACE2R). Several lines of evidence link ACE and the apolipoprotein E (apoE) isoform, E4, another risk factor for developing AD. While working directly with the SARS-CoV-2 virus is valuable, it requires working in an ABSL-3 level facility and substantially restricts studies with non-perfused tissues. SARS-CoV-2 recombinant virus-like particles (VLPs) offer an attractive way to study the pathogenesis of SARS-CoV-2 in animals, without the involvement of replicating viruses. In this application, using mice expressing human E3 or E4 under control of the mouse apoE promoter, we will investigate the mechanisms by which apoE isoform, sex, and age can affect SARS-CoV-2 VLP transport across the BBB and impact on cognition.

Public Health Relevance

Severe acute respiratory syndrome-coronavirus (SARS-CoV-2) causes a world-wide pandemic and places the aged population at an increased risk. While it has been shown this virus can enter the central nervous system, it is unclear how this occurs and whether apoE isoform or sex modulate this transport. We will investigate the impact on apoE isoform, sex, and age on the transport of SARS-CoV-2 virus-like particles across the blood- brain barrier and impact on memory and cognition.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
3RF1AG059088-01S1
Application #
10152983
Study Section
Program Officer
Wise, Bradley C
Project Start
2018-06-05
Project End
2023-03-31
Budget Start
2020-09-15
Budget End
2023-03-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Seattle Institute for Biomedical/Clinical Research
Department
Type
DUNS #
928470061
City
Seattle
State
WA
Country
United States
Zip Code
98108