Linking Defects in DNA Repair to Mitochondrial Dysfunction in Alzheimer's Disease

National Institute On Aging

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Abstract

Alzheimer's disease (AD) is a devastating neurological disease associated with progressive loss of cognitive function and physical and mental skills. We and others have observed that defects in DNA repair correlate with mitochondrial dysfunction in some 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. It is also widely accepted that persistent DNA damage leads to chronic activation of a series of downstream events including NAD+ depletion, inflammation, altered cellular bioenergetics, and mitophagy, the mechanisms whereby damaged mitochondria are removed from cells. Therapeutic interventions that target mitochondrial maintenance pathways may have utility in preventing or delaying AD pathology. Here, we propose to investigate the complex relationships between AD pathology, defective mitophagy, mitochondrial dysfunction, and defective DNA repair. We have been investigating the benefits of nicotinamide riboside, an nicotinamide adenine dinucleotide (NAD) supplement. NAD levels are lower in AD brains and treatment of AD mice with NR for 5 months increased brain NAD levels, while it reduced cytokine and inflammation, DNA damage, apoptosis, and cellular senescence markers. cGAS/Sting was increased in AD mouse brains and normalized after NR treatment. NR treatment also improved cognition and synaptic function in the APP/PS1 mutant mice. Our results suggest that NAD supplementation may offset neuroinflammation via cGAS/Sting signaling.