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Novel Genetic Models to Study the Role of Inflammation in Brain Injury-Induced Alzheimer's Pathology

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Technical Report,30 Sep 2014,29 Sep 2015

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The Cleveland Clinic Foundation Cleveland United States

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Individuals exposed to traumatic brain injury TBI are at a greatly increased risk for developing a number of neurodegenerative diseases including Alzheimers 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 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 post-injury time points. By contrast, the acute macrophage response to TBI in hTau mice is enhanced compared to brain injured controls. Brain injured mice display region specific macrophage activation at chronic time points independent of behavioral impairment. Subsequent studies revealed the presence of infiltrating monocytes near the injury cavity at acute time points and in sub-cortical structures at chronic time points in all brain injured mice.

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