The amyloid beta/A4 protein, and its precursor protein (APP), may be involved in the pathogenesis of several human neurologic diseases including Alzheimer's disease (AD) and dementia pugilistica. Epidemiological studies have shown that TBI is a risk factor in AD, and beta/A4 amyloid protein deposition has been reported within days after severe TBI in humans. The severity of dementia pugilistica correlates with the number of bouts (i.e., frequency of TBI). Recent data from our laboratory and other investigators indicate that TBI can increase the level of APP mRNA and also alter processing of APP in rats. These effects may be mediated by increased levels of cytokines (IL-1) or excessive stimulation of receptors for certain neurotransmitters (acetylcholine, excitatory amino acids). The overall goals of this research are to: 1) employ clinically relevant rodent models to describe increases and/or altered processing of amyloid precursor protein (APP) produced by traumatic brain injury (TBI), 2) examine possible mechanisms mediating these changes, and 3) determine if changes in levels and/or cleavage products of APP are reliably associated with pathological responses to TBI. The long-term goal is to develop a research program examining genomic changes regulating synthesis of proteins mediating the maintenance of enduring neurological deficits produced by TBI. CENTRAL HYPOTHESIS: TBI increases the level of APP. Subsequent production of specific pools of APP fragments are associated with pathological responses to TBI. We will perform quantitative and qualitative analyses of total APP mRNA and protein as well as isoforms of APP to achieve the following aims: 1. To perform regional analyses of total APP mRNA and protein at different times after moderate and severe TBI and to determine relationships between changes in APP, cellular localization, and light microscopic histopathology. 2.To describe regional changes in isoforms of APP mRNA and protein at different times after moderate and severe TBI to determine the temporal profile of changes in neurons and glia. 3. To determine the temporal sequences of changes in IL-1 levels and functional activation of transcription factors (i.e., Fos, Jun, HSF) induced by TBI and their correlations with APP induction. 4. To examine the effects of reduced excitotoxic responses to TBI (produced by n-methyl-d-aspartate and muscarinic receptor antagonists, or by moderate hypothermia) and reduced expression of APP (produced by IL-1 receptor antagonist) on histopathological changes as well as motor and spatial memory deficits. 5. To examine the effects of TBI on APP changes in aged rats and younger rats with a previous history of TBI and to correlate these changes with histopathological alterations as well as motor and spatial memory deficits.
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