DNA methylation in the hippocampus in rodent and primate models of aging and Alzheimer’s disease

With the aging of the world’s population, Alzheimer’s disease (AD) is a growing problem. It is caused by pathological hallmarks including amyloid β plaques and neurofibrillary tangles, but the underlying molecular mechanisms are unknown. DNA methylation, the binding of a methyl group to cytosine in the DNA, has been suggested to play a role in the development of AD. It is catalyzed by the enzyme DNA methyltransferase (DNMT) and creases a 5-methylcytosine (5mC), which generally represses gene expression. 5mC can be converted into 5hmC by ten eleven translocation (TET) enzymes and this is believed to increase gene expression. DNA methylation, DNA hydroxymethylation and DNMT3A, a member of the DNMT family involved in de novo DNA methylation, are suggested to influence cognitive functions, but their exact role in the onset and development of AD remains unknown. In this study, possible changes in these epigenetic markers in the hippocampal sub-regions (cornu ammonis 1, 2 and 3 (CA1, 2 and 3) and dentate gyrus (DG)) of several animal models for AD are examined. 5mC levels in the DG of J20 were shown to decrease with aging and Dnmt3a levels in the CA1-2 of these mice showed an age-related increase. In contrast to the J20 mice, 3xTgAD mice showed an increase in 5mC in the DG as well as an increase in Dnmt3a levels. In both the APP/PS1 mouse model and the vervets, no significant increases or decreases were detected. These results show that there are major differences in DNA methylation in hippocampal sub-regions between different animal models for AD

The impact of metabolic stressors on mitochondrial homeostasis in a renal epithelial cell model of methylmalonic aciduria

Abstract Methylmalonic aciduria (MMA-uria) is caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). MUT deficiency hampers energy generation from specific amino acids, odd-chain fatty acids and cholesterol. Chronic kidney disease (CKD) is a well-known long-term complication. We exposed human renal epithelial cells from healthy controls and MMA-uria patients to different culture conditions (normal treatment (NT), high protein (HP) and isoleucine/valine (I/V)) to test the effect of metabolic stressors on renal mitochondrial energy metabolism. Creatinine levels were increased and antioxidant stress defense was severely comprised in MMA-uria cells. Alterations in mitochondrial homeostasis were observed. Changes in tricarboxylic acid cycle metabolites and impaired energy generation from fatty acid oxidation were detected. Methylcitrate as potentially toxic, disease-specific metabolite was increased by HP and I/V load. Mitophagy was disabled in MMA-uria cells, while autophagy was highly active particularly under HP and I/V conditions. Mitochondrial dynamics were shifted towards fission. Sirtuin1, a stress-resistance protein, was down-regulated by HP and I/V exposure in MMA-uria cells. Taken together, both interventions aggravated metabolic fingerprints observed in MMA-uria cells at baseline. The results point to protein toxicity in MMA-uria and lead to a better understanding, how the accumulating, potentially toxic organic acids might trigger CKD