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Principal Investigator: Erin R Hascup
Organization: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
Fiscal Year: 2020
Award: $368,750
Funding agency: National Institute on Aging
Project Summary/Abstract
The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic
has created a healthcare crisis that was previously reserved for the accelerating Alzheimer’s
disease (AD) diagnoses. Geriatric individuals are a high risk group prone to severe infection and
death, however, a large percentage of these individuals will survive. The predilection of SARS-
CoV-2 and AD to this population indicates age-associated factors may become aggravated upon
viral infection, thereby exacerbating underlying AD symptomatology. We need a better
understanding of the long-term effects of SARS-CoV-2 infection – particularly in relation to AD
progression.
AD is an age-related neurodegenerative disorder characterized by progressive anterograde
amnesia and eventual death. Blood brain barrier (BBB) disruption is typically observed in AD
patients leading to increased vascular permeability. This disrupted microvasculature predisposes
individuals with mild cognitive impairment and AD to increased CNS infiltration by SARS-CoV-2.
Once in the CNS, SARS-CoV-2 can infiltrate host cellular components through interaction with
angiotensin converting enzyme-2 (ACE2). ACE2 is part of the renin-angiotensin system,
expressed on hippocampal neurons, and involved with learning and memory. Downregulation of
ACE2 is observed in AD patients in conjunction with elevated amyloid-β (Aβ) and tau levels.
Further internalization of this receptor upon SARS-CoV-2 neurotropism may exacerbate AD
pathology and potentiate disease progression. Viral infection can also cause host cell senescence
as a defense mechanism against viral replication. The subsequent senescence-associated
secretory phenotype (SASP) can secrete pro-inflammatory cytokines and chemokines impacting
neighboring cells and causing a deleterious feed-forward cycle propagating AD pathology and
cognitive decline.
The Aims of our current funding mechanism are designed to elucidate the role of cellular
senescence in AD. The SARS-CoV-2 emergent crisis coupled with its proclivity to infect geriatric
populations and our scientific understanding of viral infection on senescent cell burden provides
SCIENTIFIC PREMISE for the proposed studies. For this administrative supplement we
hypothesize that CNS infection of SARS-CoV-2 increases senescent cell burden thus aggravating
the development, progression, and severity of cognitive deficits in AD mouse models.
Complimentary in vitro (AIM 1) and in vivo (AIM 2) assays will be used to probe the long-term
consequences of SARS-CoV-2 infection on senescent cell accumulation andneuroinflammation,
thereby accelerating cognitive and physical AD symptomatology.
Terms: <2019 novel coronavirus><2019-nCoV><AD dementia><AD model><AD pathology><Administrative Supplement><Age><Age-Years><Aging><Alzheimer><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's diagnosis><Alzheimer's disease dementia><Alzheimer's disease diagnosis><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Alzheimers disease><Ammon Horn><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Anterograde Amnesia><Anterograde Memory Loss><Assay><Aβ><BBB disruption><Bioassay><Biologic Assays><Biological Assay><CD143 Antigens><CNS infection><COVID-19><COVID19><Carboxycathepsin><Cell Aging><Cell Body><Cell Cycle Arrest><Cell Senescence><Cells><Cellular Aging><Cellular Senescence><Central Nervous System Infections><Central Nervous System Infectious Disease><Central Nervous System Infectious Disorder><Cessation of life><Chemotactic Cytokines><Clinical><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Cornu Ammonis><Coupled><Culturing, in vitro Vertebrate, Primary><Dasatinib><Death><Defense Mechanisms><Deterioration><Development><Dipeptidyl Peptidase A><Disease Progression><Disturbance in cognition><Down-Regulation><Downregulation><Elderly><Epidemic><Exposure to><Funding Mechanisms><Glutamates><HCoV><Health><Healthcare><Hippocampus><Hippocampus (Brain)><Homologous Chemotactic Cytokines><Human><Impaired cognition><In Vitro><Individual><Infection><Infiltration><Inflammation><Inflammatory><Intercrines><Kininase A><Kininase II><Knowledge><L-Glutamate><Lead><Learning><Long-Term Effects><Longterm Effects><MT-bound tau><Memory><Metabolic><Modern Man><Nerve Cells><Nerve Degeneration><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neurocyte><Neuron Degeneration><Neuronal Transmission><Neurons><Neurotropism><Pathogenesis><Pb element><Peptidyl-Dipeptidase A><Peripheral><Phenotype><Population><Primary Cell Cultures><Primary Senile Degenerative Dementia><Proteins><QOL><Quality of life><Quercetin><Renin-Angiotensin System><Replicative Senescence><Reporting><Role><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><SIS cytokines><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Severities><Survivors><Symptoms><Vascular Permeabilities><Viral><Viral Diseases><Virus Diseases><Virus Replication><Vulnerable Populations><Wuhan coronavirus><a beta peptide><abeta><advanced age><age related neurodegeneration><age-related neurodegenerative disease><age-related neurodegenerative disorder><ages><alzheimer model><amyloid beta><amyloid-b protein><asymptomatic Alzheimer's><asymptomatic Alzheimer’s disease><axon signaling><axon-glial signaling><axonal signaling><beta amyloid fibril><blood-brain barrier disruption><bloodbrain barrier disruption><brain tissue><cell type><chemoattractant cytokine><chemokine><cognitive defects><cognitive development><cognitive dysfunction><cognitive loss><corona virus disease 2019><coronavirus disease 2019><cytokine><dementia of the Alzheimer type><design><designing><developmental><elders><experiment><experimental research><experimental study><fisetin><geriatric><glia signaling><glial signaling><glutamatergic><health care><health-span><healthspan><heavy metal Pb><heavy metal lead><high risk group><high risk population><hippocampal><human CoV><human corona virus><human coronavirus><in vivo><late life><later life><microtubule bound tau><microtubule-bound tau><mild cognitive disorder><mild cognitive impairment><mouse model><murine model><nerve signaling><neural degeneration><neural signaling><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><neuronal signaling><neurotransmission><novel><older adult><older person><pandemic><pandemic disease><prevent><preventing><primary degenerative dementia><psychological defense mechanism><receptor internalization><senescence><senescent><senile dementia of the Alzheimer type><senior citizen><severe acute respiratory syndrome-CoV><social role><soluble amyloid precursor protein><symptomatology><tau><tau Proteins><tau factor><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease><vulnerable group><τ Proteins>