Processing of Oxidative Stress in Alzheimer's Disease

Bohr, V A.

Abstract

of work: Recently, it was demonstrated (Prashad et al.) that cells from patients with familial Alzheimer disease (AD) had an altered response to fluorescent light (FL) exposure as compared to cells from unaffected individuals, suggesting that there may be some deficiency in the DNA repair processing of oxidative lesions induced by FL in AD. This project was initiated to develop a better understanding of the DNA repair capacity of AD for FL induced lesions. The formation and repair of oxidative base lesions in AD and normal fibroblasts was measured after exposure to FL using gas chromatography/mass spectrometry (GC/MS) analysis. Several oxidative DNA lesions were induced in AD and normal cells by exposure to FL. The oxidative lesions induced by FL exposure include 5-hydroxycytosine, formamidopyrimidine, and 8-hydroxy guanine. Additionally, the capacity of AD cells to repair oxidative DNA damage is being investigated using an in vitro DNA repair synthesis assay. In vitro DNA repair synthesis was carried out by whole cell extracts from AD and normal cells on plasmid DNA damaged by gamma-irradiation. This substrate was repaired efficiently by whole cell extracts from both AD and normal cells. Similar in vitro assays using plasmid DNA damaged by various oxidative sources are currently in progress.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Aging (NIA)
• Type: Intramural Research (Z01)
• Project #: 1Z01AG000735-01
• Application #: 6160490
• Study Section: Special Emphasis Panel (LMG)
• Support Year: 1
• Fiscal Year: 1997

Institution

• Name: National Institute on Aging
• Country: United States

Publications

Sykora, P; Kanno, S; Akbari, M et al. (2017) DNA polymerase beta participates in mitochondrial DNA repair. Mol Cell Biol :

Sykora, Peter; Misiak, Magdalena; Wang, Yue et al. (2015) DNA polymerase ? deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res 43:943-59

Yang, Jenq-Lin; Sykora, Peter; Wilson 3rd, David M et al. (2011) The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency. Mech Ageing Dev 132:405-11

Weissman, Lior; de Souza-Pinto, Nadja C; Mattson, Mark P et al. (2009) DNA base excision repair activities in mouse models of Alzheimer's disease. Neurobiol Aging 30:2080-1

Maynard, Scott; Schurman, Shepherd H; Harboe, Charlotte et al. (2009) Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30:2-10

Weissman, Lior; Jo, Dong-Gyu; Sorensen, Martin M et al. (2007) Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment. Nucleic Acids Res 35:5545-55

Bohr, V A; Ottersen, O P; Tonjum, T (2007) Genome instability and DNA repair in brain, ageing and neurological disease. Neuroscience 145:1183-6

Weissman, L; de Souza-Pinto, N C; Stevnsner, T et al. (2007) DNA repair, mitochondria, and neurodegeneration. Neuroscience 145:1318-29

Zhang, Peisu; Furukawa, Katsutoshi; Opresko, Patricia L et al. (2006) TRF2 dysfunction elicits DNA damage responses associated with senescence in proliferating neural cells and differentiation of neurons. J Neurochem 97:567-81

Imam, Syed Z; Karahalil, Bensu; Hogue, Barbara A et al. (2006) Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner. Neurobiol Aging 27:1129-36