Impact of APOE Genotype on Astrogliopathies in Repetitive mTBI
Abstract
Repetitive mild TBI (r-mTBI) is an environmental risk factor for Alzheimer's Disease (AD) and related dementia (ADRD). One of the hallmark features of r-mTBI is the localization of tau in astrocytes, termed tau astrogliopathies. This feature is also observed in advanced aging (ARTAG) and in FTDTau brains. The precise nature of how TBI leads to or precipitates this path towards astrogliopathy remains elusive. APOE genotype, particularly the APOE4allele, is a risk factor for sporadic ADRD cases such as AD and FTD, and is linked with increased risk for ADRD after TBI. ApoE is produced by astrocytes in the brain, but its role in promoting astrogliopathies in the context of TBI remains unknown. We have generated molecular profiles of mTBI pathogenesis in rmTBI models, collected at a range of timepoints post-injury. Our data clearly demonstrate the unique contributions from different cell types, particularly reactive astrocyte pathologies, and the critical role for microglia inflammation. Our preliminary data also suggest that APOE genotype differentially influences TBI induced astrocyte and microglia pathobiology, and this correlates with detection of pathogenic neuronal tau species in APOE4-targeted replacement (TR)mice, and those crossed with hTau knock-in mice following r-mTBI. However, none of our models (or any in the literature) has clearly demonstrated TBI dependent tau astrogliopathy. In this proposal, we plan to utilize APOE-TR mice engineered to produce non-mutant hTau in astrocytes (E2/E3/E4*GFAP-Tau),to enable us to explore the influence of APOE genotype on TBI-dependent astrogliopathy. We hypothesize that astrocytes are key to the pathobiological sequelae and lesions observed in TBI and ADRD, and this can be influenced by APOE genotype.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1193028
Entities
People
- Fiona Crawford
- Joseph Ojo
- Lauren Horne