Many established risk factors for dementia induce oxidative injury including age, amyloid Beta, hyperhomocysteinemia, and ApoE4. We have established the occurrence of oxidant injury in neurodegenerative diseases, in particular Alzheimer's disease (AD), by demonstrating overproduction of isoprostanes (IsoPs), neuroprostanes (NPs) products of free radical induced oxidation of arachidonic acid and docosahexaenoic acid, respectively. Isoketals (IsoKs) and neuroketals (NKs) are highly reactive gamma-ketoaldehydes produced by the IsoP and NP pathways, respectively. IsoKs and NKs rapidly adduct to proteins and exhibit a unique proclivity to cross link proteins. Recently, we found that pyridoxamine effectively traps and prevents IsoKs from adducting to proteins in vitro. A dominant feature of Alzheimer's disease is the accumulation of aggregated proteins. Proteasome activity is also impaired in Alzheimer's disease, which can induce apoptosis. The cause of protein aggregation, proteasome inhibition, and the relationship between these phenomena is poorly understood. Recently, we found intense IsoK immunoreactivity in hippocampal neurons in AD brains, which was absent in brains from aged-matched controls. IsoK adducted proteins are poorly degraded by the 20S proteasome and also inhibit proteasome function, lsoKs inhibit proteasome function and induce cell death at nM concentrations in neuroglial cells. These findings have engendered the hypothesis that oxidative injury in Alzheimer's disease and likely other forms of dementia produces IsoKs and NKs, which adduct to proteins and alter neuronal function, inhibit proteasome function, and induce neuronal cell death. To test this hypothesis, we will determine the levels and distribution of IsoK/NK adducts in post-mortem brains from patients with Alzheimer's disease and determine whether IsoK/NK adducts are present in CSF from AD patients. We recently established the occurrence of oxidant injury in an animal model of dementia that is associated with severe memory deficit, aged ApoE null mice overexpressing human ApoE4. We will determine the time-course of development and progression of memory deficit; increased formation of IsoPs, NPs, IsoK/NK adducts, and changes in protease activity in these animals. We will identify IsoK/NK adducted proteins in the hippocampus of AD brains and in brains of the mouse model of dementia. We will also determine the efficacy of 2 antioxidants, Tempol and lipoic acid, to suppress oxidative stress, IsoK/NK adduct formation, and mitigate the memory deficit in the mouse model. We will also explore a novel pharmacologic intervention, the ability of pyridoxamine to selectively prevent IsoK/NK adduction and mitigate the memory deficit in the mouse model.
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