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 the neuronal dysfunction seen in neurodegenerative diseases by utilizing several biological models like transgenic mice, patient post-mortem tissue and cultured lymphoblast cells from patients with neurodegenerative diseases. We are focusing on Alzheimer's disease (AD) since this is the most prevalent form of dementia in people 65 years or older. We tested the hypothesis that a DNA repair deficiency may exacerbate the symptoms and features of an AD mouse model. Specifically, we bred the 3xTgAD mouse to our DNA Polymerase Beta heterozygous mouse (PolB). PolB is an essential protein whose role is to perform the DNA synthesis step in Base Excision Repair (BER). The new mouse model, 3xTgAD/PolB displayed several important new features that the parental AD mouse model did not i.e. elevated cell death markers, altered ABeta deposition, greater mitochondrial dysfunction and worse memory and learning. These added features make the new mouse model more similar to the AD presentation seen in humans. Additionally, transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polβ(+/-) mice including abnormalities suggestive of impaired cellular bioenergetics. Mitochondria dysfunction, which likely contributes to AD pathology was more striking in the new mouse model. Together, our work and others suggest 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. Using this improved AD model, our future work is focusing on interventions that may interrupt development or delay progress of the neurodegenerative features in these mice. We also plan to generate new mouse models where a BER deficient mouse is crossed with the 3xTgAD mouse model.