Alzheimers disease (AD) is a devastating neurological disease associated with progressive loss of cognitive function as well as progressive loss of physical and mental skills. We and others have observed that defects in DNA repair correlate with mitochondrial dysfunction in the context of several human pathological conditions, including AD. There is also strong evidence that mitochondrial dysfunction contributes to prominent neuropathological features of AD and that high levels of oxidative stress and DNA damage accumulate in brain neurons from AD patients. Furthermore, it is now widely-accepted that persistent DNA damage leads 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+), inhibition of Sirtuins, and altered cellular bioenergetics. PARP1 is hyper-activated in neurons of AD patients and agents that inhibit PARP1 or increase NAD+ partially reverse phenotypic changes in cellular models of AD. Importantly, we have recently shown that depletion of NAD+ and its subsequent replenishment can alter critical aspects of AD pathology like tau phosphorylation and DNA damage 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.
