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 Alzheimers 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 tauor 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. We have begun analyzing astrocyte lesions in tissue from both mice and humans, and observe qualitative changes to astrocyte morphologies, but no quantitative data has been yet finalized. 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 also 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. These studies are still ongoing, with the latter demonstrating that factors released by injured astrocytes can directly impact on health of other glial cell types (i.e. activate stat3
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1115312
Entities
People
- Fiona Crawford
- Joseph Ojo
Organizations
- Roskamp Institute