Mitochondrial dihydrolipoyl succinyltransferase deficiency accelerates amyloid pathology and memory deficit in a transgenic mouse model of amyloid deposition
Mitochondrial dihydrolipoyl succinyltransferase deficiency accelerates amyloid pathology and memory deficit in a transgenic mouse model of amyloid deposition
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DOI：
10.1016/j.freeradbiomed.2009.07.008
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发表时间：
2009-10-01
影响因子：
7.4
通讯作者：
Beal, M. Flint
中科院分区：
文献类型：
--
作者：
Dumont, Magali;Ho, Daniel J.;Beal, M. Flint
线粒体功能障碍和氧化应激参与阿尔茨海默病（AD）的发病机制。在人类AD脑中，α-酮戊二酸脱氢酶复合物（α-KGDHC）的活性降低。KGDHC主要参与NADH的产生。它还可以参与氧化应激和活性氧（ROS）的产生。线粒体二氢硫辛酰琥珀酰转移酶（DLST）是特异于a-KGDHC的关键亚基。在培养的细胞中，减少DLST增加H2 O2诱导的ROS产生和细胞死亡。因此，我们使用淀粉样蛋白沉积的转基因小鼠模型与DLST+/-小鼠杂交，询问DLST的部分遗传缺失是否可以加速AD发病机制的发生。携带有两个突变的人类淀粉样前体蛋白的tg 19959小鼠会出现淀粉样沉积和进行性行为异常。我们将Tg 19959小鼠与2-3月龄的Tg 19959-DLST+/-同窝小鼠进行了比较，并研究了DLST缺乏对淀粉样蛋白沉积、空间学习和记忆以及氧化应激的影响。我们发现DLST+/-小鼠中α-KGDHC活性降低。我们还发现，DLST缺乏增加了淀粉样蛋白斑块负荷，A β寡聚体和硝基酪氨酸水平，并加速了雌性Tg 19959小鼠空间学习和记忆缺陷的发生。我们的数据表明，α-KGDHC可能通过增加线粒体氧化应激参与AD发病机制。(C)2009 Elsevier Inc. All rights reserved.
Mitochondrial dysfunction and oxidative stress are involved in Alzheimer disease (AD) pathogenesis. In human AD brains, the activity of the a-ketoglutarate dehydrogenase enzyme complex (alpha-KGDHC) is reduced. KGDHC is mostly involved in NADH production. It can also participate in oxidative stress and reactive oxygen species (ROS) production. The mitochondrial dihydrolipoyl succinyltransferase enzyme (DLST) is a key subunit specific to the a-KGDHC. In cultured cells, reduction of DLST increased H2O2-induced ROS generation and cell death. Thus, we asked whether partial genetic deletion of DLST could accelerate the onset of AD pathogenesis, using a transgenic mouse model of amyloid deposition crossed with DLST+/- mice. Tg19959 mice, which carry the human amyloid precursor protein with two mutations, develop amyloid deposits and progressive behavioral abnormalities. We compared Tg19959 mice to Tg19959-DLST+/- littermates at 2-3 months of age and studied the effects of DLST deficiency on amyloid deposition, spatial learning and memory, and oxidative stress. We found that alpha-KGDHC activity was reduced in DLST+/- mice. We also found that DLST deficiency increased amyloid plaque burden, A beta oligomers, and nitrotyrosine levels and accelerated the occurrence of spatial learning and memory deficits in female Tg19959 mice. Our data suggest that alpha-KGDHC may be involved in AD pathogenesis through increased mitochondrial oxidative stress. (C) 2009 Elsevier Inc. All rights reserved.