THE EFFECTS OF AGING AND NEURODEGENERATION ON APOPTOSIS-ASSOCIATED DNA FRAGMENTATION AND THE BENEFITS OF NICOTINAMIDE

In this work, the tertiary butylhydroperoxide-(t-BuOOH) treated mouse was used as a model to study the oxidative stress that is associated w ith various neurodegenerative diseases. DNA was found to be an early t arget of t-BuOOH attack. Necrosis was associated with extensive DNA fr agmentation that occurred in almost all regions of the brain within 20 min following intracerebroventricular (icy) injection of 109.7 mg/kg t-BuOOH. Apoptosis was associated with high levels of DNA fragmentatio n that was observed at 48 h after icy administration of 21.9 mg/kg t-B uOOH. Susceptibility to DNA damage was found to be age-dependent, sinc e 24-mo-old mice exhibited consistently higher and more pervasive DNA damage than 8 mo-old-mice. Extensive DNA damage was seen in various br ain regions in patients with Alzheimer disease (AD) and with both Alzh eimer and Parkinson disease (AD-ED). These results directly implicate DNA damage in neurodegeneration. The DNA fragmentation ob-served can l ead to both apoptosis and necrosis, as suggested by gel electrophoresi s. Nicotinamide, a precursor of NAD in the brain, was able to prevent DNA fragmentation induced by low-dose t-BuOOH, when coadministered wit h the toxin.