Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment.
Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment.
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DOI：
10.1093/nar/gkm605
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发表时间：
2007
影响因子：
14.9
通讯作者：
Bohr VA
中科院分区：
文献类型：
--
作者：
Weissman L;Jo DG;Sørensen MM;de Souza-Pinto NC;Markesbery WR;Mattson MP;Bohr VA
氧化应激被认为在阿尔茨海默病（AD）的发病机制中起作用，并且已经在AD患者的脑组织中观察到氧化DNA损伤增加。碱基切除修复（BER）是小碱基修饰（如烷基化、脱氨基和氧化）的主要DNA修复途径。在这项研究中，我们调查了AD患者大脑BER容量的变化。我们采用了一套功能测定，以测量BER活动的脑组织从短的死后间隔尸检的10个散发性AD患者和10个年龄匹配的控制。BER活动也测量了9名遗忘型轻度认知障碍（MCI）受试者的脑样本。我们发现AD患者大脑中的BER明显不足，这是由于DNA糖基化酶对DNA碱基损伤的处理有限，DNA聚合酶β的DNA合成能力降低。BER损伤并不局限于受损的大脑区域，在遗忘型MCI患者的大脑中也检测到了BER损伤，在遗忘型MCI患者的大脑中，BER损伤与丰富的神经元缠结相关。这些研究结果表明，BER功能障碍是AD大脑的一般特征，可能发生在疾病的最早阶段。这些结果支持了BER缺陷可能在AD的进展中起重要作用的假设。
Oxidative stress is thought to play a role in the pathogenesis of Alzheimer's disease (AD) and increased oxidative DNA damage has been observed in brain tissue from AD patients. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. In this study, we have investigated alterations in the BER capacity in brains of AD patients. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls. BER activities were also measured in brain samples from 9 amnestic mild cognitive impairment (MCI) subjects. We found significant BER deficiencies in brains of AD patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by DNA polymerase β. The BER impairment was not restricted to damaged brain regions and was also detected in the brains of amnestic MCI patients, where it correlated with the abundance of neurofibrillary tangles. These findings suggest that BER dysfunction is a general feature of AD brains which could occur at the earliest stages of the disease. The results support the hypothesis that defective BER may play an important role in the progression of AD.
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DOI：
10.1016/s0921-8777(00)00029-x
发表时间：
2000-08-30
期刊：
MUTATION RESEARCH-DNA REPAIR
影响因子：
--
作者：
Beard, WA;Wilson, SH
通讯作者：
Wilson, SH
影响因子：
4.2
作者：
Ball, M;Braak, H;Khachaturian, Z
通讯作者：
Khachaturian, Z
影响因子：
4.8
作者：
Kruman, II;Schwartz, E;Mattson, MP
通讯作者：
Mattson, MP
影响因子：
9.9
作者：
Mecocci, P;Polidori, MC;Senin, U
通讯作者：
Senin, U
影响因子：
2.9
作者：
Lovell, MA;Xie, CS;Markesbery, WR
通讯作者：
Markesbery, WR