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-? (A?) 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.
In the proposed studies, we will examine the long-term effects of COVID-19 infection on aggravating Alzheimer?s disease (AD) symptoms. We hypothesize that COVID-19 infection causes an arrested cell cycle (cellular senescence) in brain tissue that hastens the development of cognitive and physical decline in the APPNL-F/NL-F and A?PP/PS1 mouse models of AD. These experiments can help scientific knowledge by identifying how a novel viral infection may accelerate Alzheimer?s disease progression thereby identifying vulnerable populations that are more susceptible to cognitive and physical decline.
| Hascup, Erin R; Broderick, Sarah O; Russell, Mary K et al. (2018) Diet-Induced Insulin Resistance Elevates Hippocampal Glutamate as well as VGLUT1 and GFAP Expression in A?PP/PS1 Mice. J Neurochem : |
