Diffuse axonal injury (DAI) is one of the most common and important aspects of traumatic brain injury. However, little is known about the immediate and long-term consequences of this pathology, It has been shown that brain trauma increases the risk for developing Alzheimer's disease (AD), and can induce the rapid formation of amyloid-Beta (ABeta) plaques, a hallmark pathology of AD. Using a unique model of DAI in the pig developed in our laboratory, we have previously demonstrated a marked accumulation of ABeta in axons in association with ABeta plaques within days following injury. Our current preliminary data suggests that this process continues for at least six months following injury. Accordingly, ongoing axonal pathology may provide a persistent source of ABeta in the brain. In this application, we propose to evaluate mechanisms responsible for posttraumatic ABeta formation and determine the temporal disposition of ABeta and neurodegeneration. We will also evaluate the effects of reducing ABeta production on the extent of evolving pathology and, conversely, the effects of reducing axonal pathology on the extent of ABeta production and accumulation. To compliment the pig DAI model we have recently developed an in vitro model of """"""""cultured axonal injury"""""""" (CAI) that induces trauma via tensile elongation of isolated axons. With this model we propose to examine the immediate and evolving events following axon stretch-injury, including mechanisms of posttraumatic calcium influx. In concert with the pig studies, we propose to use the CAI model to evaluate mechanisms of ABeta accumulation in damaged axons following injury. Collectively, our proposed studies may improve understanding of potential mediators of secondary injury shortly following DAI and provide insight into progressive pathologies induced by brain trauma.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroscience and Disease Study Section (CND)
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Hicks, Ramona R
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University of Pennsylvania
Schools of Medicine
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