Synaptic dysfunction and loss appears central to clinical deficits in Alzheimer's disease (AD), but the causes of synapse loss and methods of intervention are poorly understood. Oxidative damage to proteins, DNA, RNA and lipids is increased in AD brain, including large increases in oxidized docosahexaenoic acid (DHA), an essential omega-3 fatty acid required for synaptic function. Our preliminary data show that a diet deficient in DHA results in CNS depletion of DHA, increased oxidative damage, caspase activation, Abeta accumulation and dramatic postsynaptic marker loss selectively in aging APPsw transgenic animals. DHA and synaptic marker losses in transgene positive animals correlate with increased oxidative damage. Our central hypothesis is that focal synaptic oxidative damage due to local Abeta42 accumulation drives a positive feedback loop resulting in increased Abeta production, oxidative damage, synaptic dysfunction and selective postsynaptic marker loss. Relevance to AD is supported by increased oxidized DHA, selective postsynaptic marker loss and flow cytometric evaluations showing increased synaptosomal apoptotic mitochondrial marker and Abeta labeling in AD vs. controls. Available results argue that supplemental Vit E, currently the standard treatment for oxidative damage in AD, may offer only limited protection against peroxynitrite, DHA oxidation, synaptic damage and clinical progression. In contrast, our animal model data show the phenolic antioxidant, curcumin, affords strong protection against multiple putative amyloid cascade endpoints including oxidative damage, inflammation (IL-1beta, TNF-a, CD11b, iNOS), amyloid accumulation, postsynaptic marker loss and cognitive deficits. By measuring the treatment's impact on CNS pathologic markers in animal models, we expect to validate accessible, but indirect or "surrogate" measures in humans that will be useful in assessing efficacy in clinical trials. We will test our central hypothesis using animal models to define optimum antioxidant treatments that ameliorate amyloidosis, oxidative damage and synaptic pathology in AD and confirm clinical relevance of the implicated biochemical pathways using AD tissue from the Neuropathology and Molecular Genetics Core.