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 (Laskowitz et al., 2002 & 2006; Lynch et al., 2005).
In a prior research grant subsidized by the Institute for the Study of Aging, we demonstrated that a controlled pneumatic closed head injury could accelerate Aâ accumulation in young APP transgenic (PDAPP) mice that otherwise would not demonstrate pathology. The reproducible deposition of Aâ in a compressed time frame is optimal for testing the effects of acute therapeutic interventions. Although there was no Aâ staining in either PDAPP/APOE3TR or PDAPP/APOE4 double transgenic animals prior to injury, we demonstrated deposition at 1 week post closed head injury. There appeared to be a primary effect of the APOE polymorphism, as APOE4/PDAPP animals demonstrated greater A‰ accumulation than APOE3/PDAPP animals following injury.
We have previously demonstrated that an apoE based therapeutic derived from the receptor binding region of the apoE holoprotein exerts anti-inflammmatory and neuroprotective effects in the injured CNS. We next tested this apoE-based therapeutic peptide in this model, and found that a single intravenous injection of apoE peptide entirely prevented Aâ deposition (4G8 staining) in PDAPP/APOE3 animals, whereas animals that received a vehicle injection demonstrated dense staining in hippocampus and cortex. These dramatic histological improvements were also associated with functional improvements in peptide-treated animals, as assessed by Rotorod testing.
These data demonstrate that administration of an apoE based therapeutic peptide has dramatic effects on reducing Aâ deposition, and may serve as a novel therapeutic strategy with the potential to modify disease course in AD patients. In the first year of this proposal, we demonstrated a drmataic effect of the apoE mimetic peptide on histological and functional outcomes in PDAPP/APOE3 animals. This effect was much less pronounced in the presence of APOE4. In the second portion of this proposal, we will clarify whether APOE4 plays a dominant negative role in promoting AD pathology, by examining the effectiveness of the apoE therapeutic in APOE3/APOE4 heterozygotes that are back-crossed to PDAPP. We will also examine strategies to optimize the beneficial effects of the apoE derived therapeutic in PDAPP/APOE4 animals, including optimizing dosing and administration. In addition assessing Aâ and amyloid burden, both histologically and biochemically, we will also assess other features of AD pathology, including neuroinflammation (gliosis and inflammatory cytokine release), and tau phosphorylation.
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