Processing of Oxidative Stress in Alzheimer

Bohr, Vilhelm A.

Abstract

of work: Studies have demonstrated that several cellular markers of oxidative stress are higher in cells from Alzheimer disease (AD) patients as compared to normal age- matched controls. These markers include oxidative damage to lipids, proteins, and DNA in various tissues from AD patients. It has been proposed that AD cells may have a defect in the DNA repair processing of oxidative base lesion leading to accumulation of DNA damage in AD cells. We have investigated the repair of oxidative base lesions using whole cell extracts from cultured AD lymphoblasts. DNA substrates containing both pyrimidine and purine lesions were obtained by treatment of plasmid with either gamma irradiation or fluorescent light (FL). Plasmid DNA containing primarily thymine glycol or 8- hydroxyguanine was prepared by damaging DNA with either OsO4 or methylene blue plus light ,respectively. The DNA substrates were purified free of strand breaks and were used in DNA repair synthesis assays. FAD cells were proficient in repair of these substrates containing various oxidative base lesions. Extracts from FAD cells repaired the plasmids damaged by gamma or FL- irradiation with equal efficiency as extracts from unaffected individuals. Furthermore, DNA damaged with methylene blue plus light and OsO4 were repaired with greater efficiency using FAD extracts (approximately 0.5-fold increase) as compared to cells from unaffected individuals. Our data indicate that the DNA damages resulting from the oxidative stresses used here are repaired efficiently in FAD cells. It is possible that the repair of specific oxidative base damages, such as that seen for thymine glycol and 8-hydroxyguanine, may be upregulated in FAD due to chronic oxidative stress which has been previously implicated in this disease. Additionally, there have been reports of unusual accummulation of oxidative DNA damage in mitochondrial DNA from patients with AD, and we are have recently developed novel techniques to study DNA repair in these organelles. We thus plan to investigate the DNA repair efficiency in mitochondrai from individuals with AD.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Aging (NIA)
• Type: Intramural Research (Z01)
• Project #: 1Z01AG000735-02
• Application #: 6097875
• Study Section: Special Emphasis Panel (LMG)
• Support Year: 2
• Fiscal Year: 1998

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