Sequelae of SARS-CoV-2 Infection in Alzheimer's Disease

Project Summary/Abstract: The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemichas created a healthcare crisis that was previously reserved for the accelerating Alzheimer'sdisease (AD) diagnoses. Geriatric individuals are a high risk group prone to severe infection anddeath, 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 uponviral infection, thereby exacerbating underlying AD symptomatology. We need a betterunderstanding of the long-term effects of SARS-CoV-2 infection - particularly in relation to ADprogression.AD is an age-related neurodegenerative disorder characterized by progressive anterogradeamnesia and eventual death. Blood brain barrier (BBB) disruption is typically observed in ADpatients leading to increased vascular permeability. This disrupted microvasculature predisposesindividuals 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 withangiotensin converting enzyme-2 (ACE2). ACE2 is part of the renin-angiotensin system,expressed on hippocampal neurons, and involved with learning and memory. Downregulation ofACE2 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 ADpathology and potentiate disease progression. Viral infection can also cause host cell senescenceas a defense mechanism against viral replication. The subsequent senescence-associatedsecretory phenotype (SASP) can secrete pro-inflammatory cytokines and chemokines impactingneighboring cells and causing a deleterious feed-forward cycle propagating AD pathology andcognitive decline.The Aims of our current funding mechanism are designed to elucidate the role of cellularsenescence in AD. The SARS-CoV-2 emergent crisis coupled with its proclivity to infect geriatricpopulations and our scientific understanding of viral infection on senescent cell burden providesSCIENTIFIC PREMISE for the proposed studies. For this administrative supplement wehypothesize that CNS infection of SARS-CoV-2 increases senescent cell burden thus aggravatingthe 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-termconsequences of SARS-CoV-2 infection on senescent cell accumulation andneuroinflammation,thereby accelerating cognitive and physical AD symptomatology.