Alzheimer's Disease (AD) and Parkinson's Disease (PD) are debilitating neurodegenerative diseases that are characterized by the deposition of protein aggregates. These aggregates are correlated with the presence of oxidative stress markers, suggesting that either the formation of the aggregate or their toxicity is mediated by oxidative stress. Based on results obtained from immunocytochemical and biochemical studies in the previous grant period, the investigators hypothesize that oxidative insult is autocatalytic: Initially generated reactive oxygen species (ROS), generate lipoxidtaion and glycoxidation products. The adduction of at least two such prominent reactive aldehyde, 4-hydroxynonenal (HNE), and glyoxal, has been observed to create new binding sites for adventitious Fe and Cu ions, in a manner that the bound metals are capable of catalyzing reduction of either O2 or H2O2, generating additional ROS. This redox cycling generates a steady flux of ROS that further oxidizes the constituents of the aggregates as well as nearby lipids and sugars, thus amplifying the initial oxidative insult. The novel aspect of the proposed hypothesis is the recognition that lipoxidative and glycoxidative modification products enhance, either directly or indirectly, the ability of the protein aggregates to generate ROS through their binding of adventitious redox active metal ions. In order to carefully characterize the chemical nature of oxidative damage induced by adventitiously-bound metals, investigators will study the effect of metal ions and aldehydic modifies on the aggregation and oxidation of A-beta, paired helical filament-tau and alpha-synuclein. A comparison of these results to the patterns of oxidative damage generated on their preformed aggregates will reveal whether aggregation inhibits or promotes individual types of oxidation. In parallel the investigators will continue the studies of the chemical nature and time course of oxidative stress revealed by immunocytochemical studies of brain autopsy material. Antibodies of defined specificity will facilitate the identification of the spatio-temporal characteristics of oxidative stress while mass spectroscopic studies will be used to identify and quantify the chemical nature of the oxidative lesions detected. The unique strength of the proposal is the interplay between the immunocytochemical studies and the chemical and mass spectroscopic characterization of specific defects. The results should provide diagnostic markers and help establish an improved rationale for pharmaceutical intervention.
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