Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer's disease.
Mitochondrial base excision repair in mouse synaptosomes during normal aging and in a model of Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2010.06.019
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发表时间：
2012-04
影响因子：
4.2
通讯作者：
Stevnsner T
中科院分区：
文献类型：
--
作者：
Gredilla R;Weissman L;Yang JL;Bohr VA;Stevnsner T
脑老化与突触衰退和认知障碍有关。氧化性DNA碱基损伤水平的增加和线粒体DNA（mtDNA）突变或缺失的积累导致线粒体功能障碍，在衰老过程和神经退行性疾病如阿尔茨海默病（AD）的发病机制中起重要作用。在线粒体中，碱基切除修复（BER）是主要的DNA修复途径，用于碱基修饰，如脱氨基和氧化，并构成避免mtDNA突变积累的重要机制。突触的功能高度依赖于线粒体，在目前的研究中，我们已经调查了BER在正常老化和AD模型中的小鼠脑突触体。突触体是由脑组织的亚细胞分离产生的膜结构中的孤立突触。它们包括整个突触前末梢以及部分突触后末梢。突触体包含摄取、储存和释放神经递质所必需的分子机制，包括突触囊泡和线粒体。在来自年轻和年老小鼠以及来自携带突变的APP、Tau和PS1（3xTgAD）的症状前和症状性AD小鼠的突触体部分中测量BER活性。在正常老化过程中，BER容量的减少，观察到在突触体部分，这是与BER蛋白质的水平下降。然而，我们没有观察到症状前和症状性AD小鼠的突触体BER活动之间的变化。我们的研究结果表明，年龄相关的BER能力的突触体部分的减少可能有助于线粒体和突触功能障碍在衰老过程中。然而，当分析全脑时，3xTgAD小鼠模型中AD样病理学的发展与突触体部分中BER机制的缺陷无关。
Brain aging is associated with synaptic decline and cognitive impairment. Increased levels of oxidative DNA base damage and accumulation of mitochondrial DNA (mtDNA) mutations or deletions lead to mitochondrial dysfunction, playing an important role in the aging process and the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD). In mitochondria, base excision repair (BER) is the main DNA repair pathway for base modifications such as deamination and oxidation, and constitutes an important mechanism to avoid accumulation of mtDNA mutations. Synaptic function is highly dependent on mitochondria, and in the current study we have investigated BER in synaptosomes of mouse brain during normal aging and in an AD model. Synaptosomes are isolated synapses in membranous structures produced by subcellular fractionation of brain tissue. They include the whole presynaptic terminal as well as portions of the postsynaptic terminal. Synaptosomes contain the molecular machinery necessary for uptake, storage, and release of neurotransmitters, including synaptic vesicles and mitochondria. BER activities were measured in synaptosomal fractions from young and old mice and from pre-symptomatic and symptomatic AD mice harboring mutated APP, Tau and PS1 (3xTgAD). During normal aging, a reduction in the BER capacity was observed in the synaptosomal fraction, which was associated with a decrease in the level of BER proteins. However, we did not observe changes between the synaptosomal BER activities of pre-symptomatic and symptomatic AD mice. Our findings suggest that the age-related reduction in BER capacity in the synaptosomal fraction might contribute to mitochondrial and synaptic dysfunction during aging. The development of AD-like pathology in the 3xTgAD mouse model was, however, not associated with deficiencies of the BER mechanisms in the synaptosomal fraction when the whole brain was analyzed.
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影响因子：
4.2
作者：
Gredilla, Ricardo;Garm, Christian;Holm, Rikke;Bohr, Vilhelm A.;Stevnsner, Tinna
通讯作者：
Stevnsner, Tinna
DOI：
10.1097/01.wcb.0000039286.37737.19
发表时间：
2003-01-01
影响因子：
6.3
作者：
Chen, DX;Minami, M;Simon, RP
通讯作者：
Simon, RP
影响因子：
4.7
作者：
Gabbita, SP;Lovell, MA;Markesbery, WR
通讯作者：
Markesbery, WR
影响因子：
7.8
作者：
Droge, Wulf;Schipper, Hyman M
通讯作者：
Schipper, Hyman M
DOI：
10.1083/jcb.121.2.305
发表时间：
1993-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hollenbeck PJ
通讯作者：
Hollenbeck PJ