Torregrosa-Muñumer R, Gómez A, Vara E, Kireev R, Barja G, Tresguerres J A F, Gredilla R
Department of Physiology, Faculty of Medicine, Complutense University, Plaza Ramon y Cajal s/n, 28040, Madrid, Spain.
University of Eastern Finland, Joensuu, Finland.
Biogerontology. 2016 Apr;17(2):325-35. doi: 10.1007/s10522-015-9612-x. Epub 2015 Sep 28.
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.
衰老加速小鼠8型（SAMP8）是一种特征明确的衰老动物模型，与对照抗衰老小鼠（SAMR1）相比，它表现出与年龄相关的早期神经退行性变，学习和记忆能力受损。在本研究中，我们调查了这种损伤是否部分归因于SAMP8小鼠大脑中线粒体DNA（mtDNA）修复能力和线粒体DNA损伤的变化。此外，我们研究了这些潜在变化是否与可能参与衰老和神经退行性变的两个主要过程的改变有关：细胞凋亡和炎症。我们观察到，主要的mtDNA修复酶之一线粒体APE1的比活性在SAMP8动物中显示出与年龄相关的降低，而在SAMR1小鼠中，线粒体APE1随年龄增加。SAMP8动物中mtAPE1活性的降低与mtDNA中DNA氧化损伤标志物8-氧代脱氧鸟苷（8oxodG）水平的增加有关。我们的结果还表明，与SAMR1小鼠相比，这些变化与SAMP8小鼠大脑中凋亡事件和炎症的过早增加有关。我们认为，在SAMP8动物中观察到的过早神经退行性表型可能至少部分归因于mtDNA氧化损伤处理的变化，这将导致凋亡和炎症过程的增强。
