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Mutations of the amyloid precursor protein (APP) and the APOE4 polymorphism are implicated in pathogenesis of AD. Neuroinflammatory mechanisms have come under increasing scrutiny for a role in AD pathology, and this may be one mechanism by which apoE isoform influences disease susceptibility. We have recently demonstrated that small peptide therapeutics derived from the receptor binding region of apoE can function like the intact apoE holoprotein to reduce glial activation and CNS inflammation in vitro and in vivo, and improve functional and histological injury after brain trauma.

The development of transgenic models of AD has allowed for the testing of novel disease-modifying therapeutic interventions. An important limitation to the use of these transgenic models is that the age-dependent development of AD neuropathology is highly variable with respect to age-of-onset and quantitative progression of pathological and functional changes. This variability complicates the assignment of changes that result from a novel therapeutic treatment as opposed to those typically normal variations in pathology and behavior observed in these transgenic models. Wide windows of variability also encourage investigators to employ months of prolonged treatments in an effort to ensure a greater likelihood that the therapeutic window has been covered. Since the testing of novel treatments is so important to developing an effective anti-AD therapy, we have recently created a murine survival closed head injury paradigm which causes reproducible deposition of amyloid pathology and functional deficits in APP transgenic mice over a defined time period. Our results are consistent with work done in other laboratories (Hartman et al., 2002) and permit a more efficient paradigm to assay for treatments affecting histology and function over a short and defined time period. A great advantage of our controlled application of closed head injury is that the rapid acquisition of AD-like pathology and behavioral changes can be induced in animals at a young age that would otherwise not demonstrate pathology.

We have recently demonstrated that a small therapeutic peptide derived from the receptor binding region of apoE downregulates glial activation and reduces the neuroinflammatory response in vitro and in vivo (Laskowitz et al., 2001, Lynch et al., 2003). We will assess whether administration of this novel therapeutic peptide reduces glial activation, amyloid deposition and improves behavioral outcomes in APP/APOE mice. These results may also translate into a novel therapeutic strategy to slow disease progression in patients with AD. In our experiments, we will use double transgenic mice that express a mutated human APP protein (the APPV717F mutation)together with either the human apoE3 or E4 protein isoforms. This will allow us to examine the interaction of APOE genotype and the APP mutation, and to determine whether there is a pharmacogenomic interaction between our therapeutic intervention and the humanized apoE background. Thus, the use of APP/APOE double transgenics in a murine model of closed head injury is an ideal method for testing the efficacy of novel therapeutic strategies such as the apoE-mimetic peptide in blocking the development of AD pathology and improving behavioral outcomes.

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