Thursday, May 19, 2022
5/19/2022
ABSTRACT Traumatic brain injury (TBI) is significantly correlated with increased risk for developing several neurodegenerative disorders, including Alzheimer’s Disease (AD) and AD-related dementia (ADRD), representing one of the most powerful environmental risk factors for AD/ADRD. Compounding these correlates is that aging is a substantial factor in the incidence and vulnerability to TBI. Owing to the complexities surrounding TBI as a progressive neurodegenerative disorder leading to AD/ADRD, the cellular mechanisms potentially underlying the aging brain’s susceptibility to acquire degenerative responses remains elusive. To date, the bulk of published findings related to TBI-related Alzheimer’s-like impairments have been examined using young adult and predominantly male rodents, which does not accurately model the greatest at-risk population in humans. However, our aging TBI model recapitulates several correlates of Alzheimer’s like impairments including chronic memory impairment, exacerbated neuroinflammation, gliosis, phosphorylated tau, as well as microglial phenotypes previously documented in both human’s and mouse models of Alzheimer’s disease. Guided by preliminary findings, our overarching hypothesis is that in the aging brain following TBI, RelA drives exacerbated astrocyte responses, underlying the aging brain’s susceptibility for persistent decremental outcomes related to homeostatic astrocyte susceptibility, neuroinflammation, and neural network dysfunction. We believe these altered responses, initiated by TBI in the aging brain ultimately manifest in correlates characteristic of progressive neurodegeneration associated with AD/ADRD. We will pursue three aims to test this hypothesis using novel genetic models for targeting astrocytes in young and aged mice to determine 1.) The susceptibility of aged astrocytes to lose critical homeostatic features following TBI, 2.) The ability of astrocytes to regulate the conversion of microglia towards decremental AD-associated inflammatory phenotypes following TBI, and 3.) The role of astrocytes in the vulnerability of synaptic circuitry and impaired memory, a critical hallmark associated with TBI/ADRD. Cumulatively, these studies will help to elucidate both the cellular and molecular substrates through which the aging brain’s response to TBI facilitates progressive neurodegenerative sequelae that can eventually lead to AD/ADRD. Our salient findings will ultimately determine the extent to which RelA is a critical mediator in these AD-associated sequelae with the potential to elucidate new therapeutic targets toward their prevention.
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