Glial Cell Dysfunction in Neurodegenerative Sequelae of Repetitive Mild Traumatic Brain Injury
Abstract
The precise nature of how TBI leads to or precipitates ADRD pathogenesis is not understood. To address this problem we have, generated molecular profiles of AD and TBI pathogenesis in preclinical models at a range of ages/timepoints post-injury respectively, in order to identify molecules and pathways that are common to both AD and TBI and to correlate these with longitudinal changes in cognition and in the neuropathological landscape. Our analyses have highlighted the critical role of neuroinflammation after TBI, the particular significance of microglial responses. Understanding TBI neurodegeneration, and the triggers that encourage the pathogenic sequelae of TBI to follow paths toward ADRD, will be critical to the identification of effective therapeutic approaches. We have established and characterized a preclinical model of mTBI which has been validated by our clinical collaborators and which demonstrates lifelong neuroinflammatory responses and cognitive dysfunction following repetitive mTBI at a young age. We consider that repetitive mTBI induces significant and persistent changes in the microglial population over time after injury with lifelong consequences on the neuroinflammatory milieu. These microglial responses are critical to TBI neurodegeneration and in the context of other potentially pathogenic proteins such as tau or amyloid, ADRD pathobiology can be triggered. This proposal will focus on the details of microglia pathobiology in mouse models and human cases of r-mTBI and ADRD proteinopathies. We will utilize a novel single cell array approach to interrogate the gene expression and transcript profiles in a homogenous population of resting and/or activated microglia. We will address how microglia pathobiology contributes to the relationship between TBI neurodegeneration and ADRD proteinopathies, and what role young vs aged microglia play in precipitating sequelae subsequent to TBI.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1163335
Entities
People
- Fiona Crawford