313 - Age-dependent changes in human cortex antioxidant and methylation metabolic pathways and their implications for neurodegenerative disorders

Abstract

Oxidative stress and impaired methylation, including increased levels of homocysteine (HCY), are well-recognized for their contribution to the pathogenesis of Alzheimer's disease (AD). Metabolic pathways for production of the antioxidant glutathione (GSH) and the methyl donor S-adenosylmethionine (SAM) are interrelated and connected by transsulfuration of homocysteine to cysteine (Fig. 1). These pathways are uniquely regulated with age in human brain and their dysfunction can result in neurological disorders manifested across the lifespan. Levels of antioxidant and methylation metabolites and individual vitamin B12 species were measured in postmortem human frontal cortex across the lifespan, along with mRNA levels of the folate and vitamin B12-dependent enzyme methionine synthase (MS), which converts homocysteine to methionine. In control subjects, expression of the MS gene (mtr) showed a remarkable 400-fold progressive decrease with age, in conjunction with alternative splicing that increases its sensitivity to oxidative stress inhibition. Levels of the MS cofactor methylcobalamin (methylB12) were >10-fold lower in 60-80 yo subjects vs. 0-20 yo subjects, accompanied by higher levels of HCY and lower levels of SAM, indicative of an age-dependent decrease in methylation. By contrast, levels of cystathionine decreased with age, indicative of increased transsufuration. Autism and schizophrenia subjects exhibited premature changes in MS expression, methylB12 and transsulfuration. Normal aging of human frontal cortex is associated with progressive changes in methylation and antioxidant metabolism, and deviations from this normal progression may be associated with AD. Providing metabolic support for brain methylation appears to be a promising approach to reducing the risk and progression of AD.