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. The base excision repair (BER) pathway repairs oxidative DNA damage, such as base modifications, which arise because of reactive oxygen species (ROS). DNA polymerase Beta (PolB) is responsible for the DNA synthesis step in the BER pathway. 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, and worse memory, learning, and smelling deficits. We propose 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. The various parts of the hippocampus, CA1, CA2, CA3 and DG are differentially susceptible to AD pathology. To investigate these regional differences spatial transcriptomics was applied to the brains of 3xTgAD and 3xTgAD/PolB-heterozygous mouse models. Our analysis identified Bok, in the CA3 region, as spatially deregulated at both the mRNA and protein levels. We also identified a multifunctional kinase, Sgk1, as a differentially expressed gene only in the AD DNA repair-deficient mice.