Processing Of Oxidative Stress In Alzheimer

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

We are testing the hypothesis that the accumulation of oxidative DNA damage contributes to neuronal dysfunction. These studies employ multiple model systems including 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. Reactive oxidative stress, ROS, causes persistent DNA damage leading to chronic activation of poly (ADP-ribose) polymerase-1 (PARP1), which in turn triggers a series of downstream events including depletion of nicotinamide adenine dinucleotide (NAD+), and increased inflammation. We previously showed that agents that inhibit PARP1 or increase NAD+ partially reverse phenotypic changes in cellular models of AD. While replenishment of NAD+ via nicotinamide riboside, can improve critical aspects of AD pathology like cognition, NLRP3 inflammasome expression, cGAS/STING activation, neuroinflammation, and senescent cell accumulation. Based on these observations, we propose to investigate the complex relationships between AD pathology, persistent depletion of NAD+, defective mitophagy, mitochondrial dysfunction, and altered or defective DNA repair.