Epigenetic mechanisms that include DNA methylation and histone modifications profoundly influence gene expression and also appear to be altered in aging. A better understanding of these mechanisms in the brain may point to novel targets for the therapy/prevention of aging-associated central nervous system pathologies. Over the last four years of funding, studies from this laboratory have established that the brain expression of 5-lipoxygenase (5-LOX), an inflammatory enzyme, increases during aging, is stimulated by glutamate receptor activation and by glucocorticoids, and might be associated with neurodegeneration, possibly in Alzheimer's disease (AD). Others have shown that 5-LOX knockout in a mouse model of Alzheimer's disease, the Tg2576 mouse, and decreases amyloidosis. Recent preliminary data indicate that neuronal 5-LOX expression increases following changes in the methylation state of CpG islands in 5-LOX promoter (e.g., by a hypomethylating drug 5-aza-2'-deoxycytidine) or after altered histone acetylation (e.g., by histone deacetylases - HDACs - inhibitors). In this proposal, we hypothesize that epigenetic mechanisms are altered in aging brain neurons and are responsible for the regulation of brain 5-LOX expression; 5-LOX expression is triggered by decreased methylation at the 5-LOX promoter and/or altered histone acetylation and methylation at the 5-LOX gene. We propose the following three specific AIMs: 1) Investigate in mice the effects of aging on a) brain DNMT1 and HDACs expression, b) brain region-specific 5-LOX promoter methylation, and c) 5-LOX-related histone acetylation and methylation; 2) In primary neuronal cultures, test the in-vitro effects of cell maturation/aging on neuronal DNMT1 and HDACs expression, 5-LOX promoter methylation, and 5-LOX-related histone acetylation and methylation; and 3) Using primary neuronal cultures, investigate the role of DNMT1 and HDACs inhibition/knockdown in 5-LOX expression. The research outlined in this grant proposal is designed to provide relevant data in support of our hypothesis that an epigenetic neuronal alteration is a putative factor that predisposes the aging brain to display an upregulated expression of the 5-LOX gene. The proposed experiments may corroborate the hypothesis that epigenetic mechanisms are involved in brain aging. ? ? ?
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