Our main objectives are 1) to understand metabolic cascades involving beta amyloid (Ap) and amyloid precursor protein (APR), and inflammatory (IL-1P) and cell death (caspases, Fas and PARP) pathways that contribute to impaired functional outcome after traumatic brain injury (TBI), and 2) to examine novel therapeutic approaches designed to ameliorate the detrimental consequences of these cascades. A central premise of our proposal is the link between TBI and Alzheimer's disease (AD) pathology, involving inflammatory reaction with pathologically elevated levels of Ap, which in TBI may increase the risk for AD. We have a unique perspective, having expertise in the pathobiology of AD, human TBI, and animal models of controlled cortical injury (CCI), and propose a multi-level, translational approach using complementary in vitro and in vivo TBI model paradigms, and brain tissue and CSF samples from TBI patients for validation of similar metabolic cascades. We will focus specifically on the relationship between injury-induced changes in caspase activation and amyloid APP metabolism, production of toxic APP derivatives Apl-40 and Apl-42, and activation of cell death pathways. Our in vitro and in vivo models will use mice carrying the human, not mouse, Ap sequence (hA(3);a novel model to study soluble Ap in rodent TBI. IL-1P treated brain cell cultures will serve to investigate mechanism of change in APP and Ap metabolism. In vivo, we will assess neurological and functional outcome (including behavioral variables and cerebral blood flow, neuronal loss, and synaptic integrity) in our well established CCI model followed by interventions with caspase inhibitors (to prevent acute cell loss) and HMG-reductase inhibitors (statins, to attenuate sub-acute/chronic inflammation, hypoperfusion and amyloidosis). Statins (now in AD clinical trials) are the main therapeutic intervention in this proposal, because of their beneficial effects on many aspects of the trauma cascade (anti-inflammation, enhancement of cerebral blood flow), and because of preliminary data suggesting efficacy in reducing post- TBI amyloidogenesis and improving neurological outcome. These experimental studies and complementary analyses of human TBI samples will provide novel data on the role of Ap in TBI pathology, and hasten the development of clinical statin intervention trials in human TBI.
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