While traumatic brain injury is one of the leading causes of death and disability, mounting evidence suggest that brain trauma may also initiate insidiously progressive neurodegenerative processes. Brain trauma is a risk factor for developing Alzheimer's disease (AD) and can induce the acute formation of plaques composed of amyloid beta (Abeta), a primary brain pathology of AD. In the first four years of this grant using animal models of brain trauma, we have observed remarkable prolonged cognitive deficits, brain atrophy, neuron death, axon degeneration, and gliosis following injury. We have also made a novel finding of Abeta accumulation following experimental brain trauma. In the current application, we propose to use our experimental paradigms to further explore potential mechanisms and modulation of age-dependent neurodegenerative changes following brain trauma. Specifically, we propose to 1) continue our evaluation of the long-term effects of brain trauma on cognitive status and histopathology, 2) examine the long-term efficacy of brain trauma therapies, 3) evaluate the effects of age at the time of brain trauma on outcome, 4) evaluate the potential neurotoxicity of Abeta production following brain trauma. Success of these studies may reveal mechanistic links between brain trauma, age and neurodegenerative processes and provide a basis for the development of new therapeutic strategies.
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