Document text
Principal Investigator: William E. Van Nostrand
Organization: UNIVERSITY OF RHODE ISLAND
Fiscal Year: 2024
Award: $196,875
Funding agency: National Institute on Aging
Although the pandemic phase of SARS-CoV-2 infections has diminished the disease remains highly
endemic in the US population with current weekly hospitalizations from infection remaining in the thousands and
significant morbidity. Further, there is always the risk that new SARS-CoV-2 variants may arise that are more
transmissible and/or pathogenic. Therefore, SARS-CoV-2 infections will remain a significant health issue in the
US for the foreseeable future. Although SARS-CoV-2 infection is largely viewed as a respiratory disease there
is substantial evidence that SARS-2-CoV-2 infection is a “vascular disease” caused by endothelial cell uptake of
the virus via angiotensin converting enzyme 2 (ACE2) that can affect various organs including the brain. With
regards to the cerebral vasculature, SARS-CoV-2 infection can cause coagulopathy and local thrombotic events
in the brain including ischemic and hemorrhagic stroke. How other cerebral vascular diseases interact with
SARS-CoV-2 infections is poorly understood.
Cerebral amyloid angiopathy (CAA) is a common amyloidal form of cerebral small vessel disease of the
elderly that is characterized by the accumulation of fibrillar amyloid b-protein (Ab) in blood vessels of the brain.
CAA is also a frequent vascular comorbidity in patients with Alzheimer’s disease and related disorders (ADRD).
Cerebral vascular accumulation of Aβ can result in perivascular neuroinflammation, cerebral infarction,
microbleeds and intracerebral hemorrhages. Because of these cerebral vascular insults, CAA is a significant
cause of vascular-mediated cognitive impairment and dementia (VCID). Recently, we generated a novel
transgenic rat model for CAA, designated rTg-D, that recapitulates many of the pathological features of the
disease in humans including cortical and meningeal vascular amyloid, cerebral microbleeds, small vessel
occlusions, and VCID. The rTg-D rat model provides a useful platform for investigating the pathogenesis of CAA
and the impact of comorbidities.
There are reports in the literature indicating that SARS-CoV-2 infection can impact CAA in a highly
detrimental manner promoting hemorrhagic events. Yet despite this link the effects of SARS-CoV-2 infection on
the course of pathology of CAA and other ADRDs remains largely unknown. Thus, the goal of this R21
exploratory proposal is to investigate the impact of SARS-CoV-2 infection on the emergence,
progression and severity of CAA in the novel rTg-D transgenic rat model of CAA. To accomplish this goal,
we propose two specific aims. First, we will determine if the SARS-CoV-2 spike 1 protein accelerates the
emergence and progression CAA and associated pathologies in younger rTg-D rats. Second, we will determine
if the SARS-CoV-2 spike 1 protein exacerbates CAA associated vasculopathies in aged rTg-D rats. Our studies
will combine quantitative pathological measures and transcriptomic approaches in a novel preclinical model of
CAA to identify key elements of activation pathways that are shared between CAA and SARS-CoV-2 infection.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><ACE2><AD related dementia><ADRD><Acceleration><Acute><Affect><Alzheimer beta-Protein><Alzheimer's Amyloid beta-Protein><Alzheimer's amyloid><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease patient><Alzheimer's disease related dementia><Alzheimer's patient><Amentia><Amyloid><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Apoplexy><Aβ><Bleeding><Blood Coagulation Disorders><Blood Vessels><Brain><Brain Nervous System><Brain 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decline><Cognitive function abnormal><Common Rat Strains><Communicable Diseases><Congophilic Angiopathy><Dementia><Disease><Disorder><Disturbance in cognition><Elderly><Elements><Encephalon><Endothelial Cells><Event><Future><Goals><Health><Hemorrhage><Hospital Admission><Hospitalization><Human><Impaired cognition><Infarction><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Intervention><Intervention Strategies><Intracerebral Hemorrhage><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Investigation><Ischemia><Ischemic Stroke><Life><Link><Literature><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Measures><Mediating><Meningeal><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological Manifestations><Neurological Signs and 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