The objectives of this Project are two-fold. First, in parallel with Project by Griffin, we will continue to study the effect of survival time and of gene polymorphisms on the manifestation of specific pathological features in traumatic brain injury which mimic the pathology of Alzheimer's disease (AD) in the belief that this will offer valuable insights into the early molecular mechanisms underlying the development of Alzheimer-type pathology. We hypothesis that the genotype of an individual modulates the extent of Abeta deposition and expression of glia-derived cytokines. Seen in the brain post-injury. Having already established that the apolipoprotein E (ApoE) genotype is important in modulating post-traumatic pathology, we will study the molecular basis of this effect in a novel in vivo paradigm of Abeta-induced neurotoxicity. Tissue from a large cohort of head-injury patients with different post-injury survival times and from non-injured control patients will be genotyped with respect to the polymorphisms in genes in the interleukin-1 gene cluster on chromosome 2.
Aim 1 will determine quantitatively the changes in expression of the glia-derived inflammatory cytokines IL-1, IL-6, and S100beta throughout the brain after fatal head injury.
Aim 2 will assess whether alterations in cytokine immunoreactivity following head injury are spatially and temporally correlated with changes in proteins that are important in the pathogenesis of AD.
Aim 3 will determine whether inter-individual variation in the extent of the inflammatory reaction to head injury is associated withy specific polymorphisms in the genes encoding ApoE and IL-1.
Aim 4 will investigate the mechanisms by which ApoE4 increases susceptibility to AD using an in vivo model of Abeta-induced neurotoxicity. Results should allow us to determine if genotype affects post-trauma pathology and will provide information on how ApoE4 produces its effects at the molecular level. The effect of genetic makeup on the extent of the inflammatory activity in the brain will be an important factor in predicting long-term sequelae of head injury (i.e., AD) and in targeting any potential therapies for the disease.
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