COBRE: UND: CARBONYL DETOXIFICATION IN CNS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's disease (AD) and other devastating chronic neurodegenerative disorders such as Parkinson's disease (PD) involve multiple factors such as advancing age, genetic background, and environmental factors. At the biochemical level these diseases are marked by elevations in oxidative damage to DNA, lipids, and proteins, and mitochondrial dysfunction. Oxidative damage leads to the formation of toxic products. In particular, oxidative damage to lipids generates numerous cytotoxic carbonyls. We hypothesize that the detoxification of carbonyls such as 4-hydroxynonenal (HNE) is a factor in the pathogenesis of neurodegenerative diseases and that alterations of carbonyl metabolism modifies the potency of cytotoxic insults. These hypotheses will be tested in the following specific aims: (1) determine the metabolism of HNE in CNS tissue. This will involve analyzing the metabolic fate of HNE in rat brain slices and endogenous levels of HNE metabolites in human brain, (2) define whether modulation of mitochondrial, class 2 and class 5 aldehyde dehydrogenase activity alters the potency of cytotoxic insults. This will involve the production of stable, transgenic human, neuronal cell lines and primary cultures of adult, rat astrocytes, (3) determine whether carbonyl detoxification can be pharmacologically elevated in the CNS as a potential therapeutic measure. This will involve the in vitro and in vivo screening of monofunctional enzyme inducers. The data gathered from the successful completion of these specific aims will provide new understanding of the pathways by which the CNS detoxifies harmful carbonyls. These data may lead to the formation of new preventative and therapeutic strategies for neurodegenerative disease.