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

National Institute On Aging

Investigators

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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 evaluated the impact of overexpression of Ogg1 in mitochondria using the mtOgg1 mouse model and cell lines. We showed that elavated Ogg1 could reverse age-associated inflammation and improve function. Additionally, we observed sex differences with respect to inflammation as old male mtOgg1 mice showed decreased inflammation. Interestingly female mice did not respond to mtOgg1 overexpression. We are continuing to explore the role Ogg1 plays in AD pathophysiology. We continue to investigate the relationship between oxidative damage and cellular dysfunction in AD. Compromised autophagy, including impaired mitophagy and lysosomal function, is thought to play pivotal role in the development and progression of AD. Urolithin A (UA) is a gut microbial metabolite of ellagic acid shown to stimulate mitophagy. We are evaluating long-term UA treatment to determine if it significantly improves learning and memory, olfactory function, and synaptic function of neurons in different AD transgenic mice. At the cellular level, we are interrogating whether UA modulates lysosomal function, Abeta and tau levels, tau phosphorylation status, oxidative damage, and markers of neuroinflammation. These studies will expand our understanding of UA biology and further explore whether it is a candidate for AD therapy.