title: Reduced apurinic/apyrimidinic endonuclease 1 activity and increased DNA damage in mitochondria are related to enhanced apoptosis and inflammation in the brain of senescence- accelerated P8 mice (SAMP8).
abstract: The senescence- accelerated mouse prone 8 (SAMP8) is a well- characterized animal model of senescence that shows early age- related neurodegeneration with impairment in learning and memory skills when compared with control senescence- resistant mice (SAMR1). In the current study, we investigated whether such impairment could be partly due to changes in mitochondrial DNA (mtDNA) repair capacity and mitochondrial DNA damage in the brain of SAMP8 mice. Besides we studied whether these potential changes were related to modifications in two major processes likely involved in aging and neurodegeneration: apoptosis and inflammation. We observed that the specific activity of one of the main mtDNA repair enzymes, the mitochondrial APE1, showed an age- related reduction in SAMP8 animals, while in SAMR1 mice mitochondrial APE1 increased with age. The reduction in mtAPE1 activity in SAMP8 animals was associated with increased levels of the DNA oxidative damage marker 8oxodG in mtDNA. Our results also indicate that these changes were related to a premature increase in apoptotic events and inflammation in the brain of SAMP8 mice when compared to SAMR1 counterparts. We suggest that the premature neurodegenerative phenotype observed in SAMP8 animals might be due, at least in part, to changes in the processing of mtDNA oxidative damage, which would lead to enhancement of apoptotic and inflammatory processes.
authors.affiliation: Department of Physiology, Faculty of Medicine, Complutense University, Plaza Ramon y Cajal s/n, 28040, Madrid, Spain.|University of Eastern Finland, Joensuu, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Torregrosa-Muñumer
authors.affiliation: Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Gómez
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, Madrid, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Vara
authors.affiliation: Department of Physiology, Faculty of Medicine, Complutense University, Plaza Ramon y Cajal s/n, 28040, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Kireev
authors.affiliation: Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University, Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Barja
authors.affiliation: Department of Physiology, Faculty of Medicine, Complutense University, Plaza Ramon y Cajal s/n, 28040, Madrid, Spain.
authors.forename: J A F
authors.initials: JA
authors.lastname: Tresguerres
authors.affiliation: Department of Physiology, Faculty of Medicine, Complutense University, Plaza Ramon y Cajal s/n, 28040, Madrid, Spain. rgredilla@med.ucm.es.
authors.forename: R
authors.initials: R
authors.lastname: Gredilla
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology*; D051379:Mice
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: 8-Hydroxydeoxyguanosine; Aging; Apoptosis; Inflammation; Mitochondrial DNA repair; Neurodegeneration; SAMP8