Novel Genetic Models to Study the Role of Inflammation in Brain Injury-Induced Alzheimer's Pathology
Annual rept. 30 Sep 2012-29 Sep 2013
CLEVELAND CLINIC FOUNDATION OH
Pagination or Media Count:
Individuals exposed to traumatic brain injury TBI are at a greatly increased risk for developing a number of neurodegenerative diseases including Alzheimer s disease AD. TBI promotes the development of the pathological hallmarks of AD including production and extracellular deposition of the beta -amyloid peptide in senile plaques and intracellular aggregation of hyperphosphorylated, microtubule-associated protein tau MAPT in neurofibrillary tangles NFTs. Several lines of evidence suggest that altered monocyte infiltration and microglial activation may be directly involved in the pathogenesis of both beta-amyloid and MAPT pathologies. The primary hypothesis to be tested in the current studies is that TBI induces infiltration of peripheral monocytes as well as acute and local activation of brain microglia within the injured brain and that these two cell types play roles distinct from each other in inducing both beta-amyloid pathologies and MAPT phosphorylation and aggregation leading to chronic pathological conditions that pre-dispose individuals exposed to TBI to develop AD later in life. Here we report that TBI results in brain cavitation and a widespread neuroinflammatory response including microglial activation and monocyte infiltration. Interestingly, the acute macrophage response to TBI is reduced in a mouse model of amyloid pathology R1.40 compared to control mice however, long-term behavioral outcome and neurodegeneration are worse at chronic postinjury time points. By contrast, pilot data examining TBI in hTau mice revealed increased phosphorylation of tau within neurons as well as enhanced microglial activation including swollen cell bodies and thickened processes when compared to brain injured controls. Recent data suggests that the macrophage response is also enhanced in brain injured hTau mice at acute postinjury time points.
- Anatomy and Physiology
- Medicine and Medical Research
- Stress Physiology