Astroglia Pathobiology in the Neurodegenerative Sequelae of Repetitive Mild Traumatic Brain Injury
Abstract
For many years TBI has been known to be a risk factor for later life neurodegenerative diseases, such as Alzheimer's Disease Related Dementias (ADRD), but the precise nature of how TBI leads to or precipitates these conditions (or different pathological substrates) is not understood. We have spent years developing and characterizing mouse models of r-mTBI that demonstrate lifelong behavioral and neuropathological features of human TBI and are thus relevant models in which to generate data that will translate to human patients. In our mouse model, we observe dramatic increases in reactive astrocyte cells, and these increases last for life. We thus hypothesized that repetitive mTBI induces significant and persistent changes to reactive astrocyte populations after injury and that these reactive astroglial responses are critical to TBI neurodegeneration and, in the context of other potentially pathogenic proteins such as tau or amyloid, distinct ADRD proteinopathies can be triggered. Here we propose neuropathological analyses of human autopsy cases of TBI, ADRD, and from the brains of normal mice and mice producing potentially pathological tau and amyloid proteins, at a range of timepoints following repetitive mild TBI. This year, we began exploring the role of astrocytes in inducing and driving pathogenesis by utilizing novel mechanistic approaches in our mouse models, involving adoptive cell transfer of TBI reactive glial cells into nave mice, and utilizing ex vivo functional assays to closely study whether reactive astrocytes in the injured brain can damage other healthy un-injured neural and vascular cells. We also began to apply our state of the art single cell genomic analyses to identify astrocyte specific changes at the gene level. These studies are almost completed, and we have generated data on three mouse models interrogated.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1187879
Entities
People
- Fiona Crawford
- Joesph Ojo
- Lauren Horne
Organizations
- Roskamp Institute