Processing Of Oxidative Stress In Alzheimer

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We are testing the hypothesis that the accumulation of oxidative DNA damage contributes to neuronal dysfunction seen in neurodegenerative diseases by utilizing multiple model systems like transgenic mice, cultured cells and C. elegans. We are focusing on Alzheimer's disease (AD) since this is the most prevalent form of dementia in people 65 years or older. The base excision repair (BER) pathway repairs oxidative DNA damage, such as base modifications, which occur spontaneously or from attack by reactive oxygen species (ROS). DNA polymerase Beta (PolB) is responsible for the DNA synthesis step in the BER pathway, which can be rate limiting. We observed decreased expression of PolB in AD patients so we bred the 3xTg AD mouse to our DNA Polymerase Beta heterozygous mouse (PolB) to create a new mouse model, 3xTgAD/PolB+/-. This new AD strain displayed several important new features that the parental AD mouse model did not. We observed elevated cell death markers, altered ABeta deposition, greater mitochondrial dysfunction, worse memory, learning, and smelling defects. These added features make the new mouse model more similar to the AD presentation seen in humans. Together, our work and others suggest that deficiencies in BER enzymes might contribute to the accumulation of oxidative damage in both nuclear and mitochondria DNA of AD patients and contribute to disease progression. In our 3xTg/PolB model, we have shown that NAD supplementation normalized key AD features like phospho-tau, memory and learning deficits. In part, we believed this is due to increased DNA repair and improved mitochondrial function and mitophagy. We have shown that human AD patient brain cells and cultured neurons display mitochondrial disfunction. Thus, we sought to evaluate whether mitophagy enhancers like NAD supplementation, urolithin A or actinonin could also improve AD features in AD models. Here we used APP/PS1 mice and A or tau C. elegans AD models. Mitophagy stimulators were effective at improving memory in worms and mice. Importantly, we observed increased phagocytic activity of microglia and reduced neuroinflammation in APP/PS1 mice following administration of urolithin A or actinonin. We had previously observed similar findings with NAD supplementation in 3xTgAD mice. In both tau overexpressing human neuronal cells and 3xTgAD mice, mitophagy induction specifically decreased the appearance of hyperphosphorylated tau, a major marker of AD pathology. Encouraged by these results we are continuing to characterize the benefits of mitophagy induction in AD models and other neurodegenerative diseases.