5-methyldeoxycytidine and Alzheimer-Disease

Increased production of hydroxyl radical is the main source of oxidative damage in mammalian DNA that accumulates in Alzheimer's disease (AD). Reactive oxygen species (ROS) react with both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) to generate 8-hydroxy-2'-deoxyguanosine (8-OHdG), both of which can be measured in the urine. Knowledge of this pathway has positioned measurement of urine 8-OHdG as a reliable index of DNA oxidation and a potential biomarker target for tracking early cellular dysfunction in AD. Furthermore, epigenetic studies demonstrate decreased global DNA methylation levels (e.g. 5-methyl-2'-deoxycytidine, 5-mdC) in AD tissues. Moreover, stress hormones can activate neuronal oxidative stress which will stimulate the release of additional stress hormones and result in damages to hippocampal neurons in the AD brain. Our previous work suggests that treating AD transgenic mice the type-1 corticotropin-releasing factor receptor (CRFR1) antagonist, R121919, to reduce stress signaling, prevented onset of cognitive impairment, synaptic/dendritic loss and Aβ plaque accumulation. Therefore, to investigate whether levels of DNA oxidation can be impacted by the same therapeutic approach, urine levels of hydrogen peroxide, 8-OHdG, 5-mdC and total antioxidant capacity (TAC) were analyzed using an AD Tg mouse model. We found that Tg animals had an 80% increase in hydrogen peroxide levels compared to wild type (Wt) counterparts, an effect that could be dramatically reversed by the chronic administration with R121919. A significant decrease of 8-OHdG levels was observed in Tg mice treated with CRFR1 antagonist. Collectively our data suggest that the beneficial effects of CRFR1 antagonism seen in Tg mice may be mechanistically linked to the modulation of oxidative stress pathways.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Alzheimer Disease; Animals; Antioxidants; Behavior, Animal; Biomarkers; Deoxycytidine; Deoxyguanosine; DNA; Enzyme-Linked Immunosorbent Assay; Female; Hydrogen Peroxide; Male; Mice, Transgenic; Oxidation-Reduction; Pyrimidines; Receptors, Corticotropin-Releasing Hormone

The DNA of brain cortex obtained from autopsy specimens of eight patients with Alzheimer's disease and eight controls was examined for content of normal and abnormal bases. DNA, purified by hydroxyapatite chromatography, was hydrolyzed under mild conditions and the deoxynucleosides were measured by high performance liquid chromatography (HPLC). No differences in the mole percentages of deoxynucleosides in DNA were detected in patients with Alzheimer's disease compared to controls, nor were abnormal deoxynucleosides found. Restriction-nuclease digests examined by agarose gel electrophoresis also showed no changes. Thus, diffuse and persistent damage to the DNA in brain in Alzheimer's disease was not detected by these methods.

Topics: Aged; Alzheimer Disease; Cerebral Cortex; Deoxyadenosines; Deoxycytidine; Deoxyguanosine; Deoxyribonucleosides; DNA; Humans; Middle Aged; Thymidine