Mitochondrial and Molecular Medicine and Genetics, University of California Irvine, Irvine, CA, USA.
J Alzheimers Dis. 2010;20 Suppl 2(0 2):S293-310. doi: 10.3233/JAD-2010-100351.
Increasing evidence is implicating mitochondrial dysfunction as a central factor in the etiology of Alzheimer's disease (AD). The most significant risk factor in AD is advanced age and an important neuropathological correlate of AD is the deposition of amyloid-beta peptide (Abeta40 and Abeta42) in the brain. An AD-like dementia is also common in older individuals with Down syndrome (DS), though with a much earlier onset. We have shown that somatic mitochondrial DNA (mtDNA) control region (CR) mutations accumulate with age in post-mitotic tissues including the brain and that the level of mtDNA mutations is markedly elevated in the brains of AD patients. The elevated mtDNA CR mutations in AD brains are associated with a reduction in the mtDNA copy number and in the mtDNA L-strand transcript levels. We now show that mtDNA CR mutations increase with age in control brains; that they are markedly elevated in the brains of AD and DS and dementia (DSAD) patients; and that the increased mtDNA CR mutation rate in DSAD brains is associated with reduced mtDNA copy number and L-strand transcripts. The increased mtDNA CR mutation rate is also seen in peripheral blood DNA and in lymphoblastoid cell DNAs of AD and DSAD patients, and distinctive somatic mtDNA mutations, often at high heteroplasmy levels, are seen in AD and DSAD brain and blood cells DNA. In aging, DS, and DSAD, the mtDNA mutation level is positively correlated with beta-secretase activity and mtDNA copy number is inversely correlated with insoluble Abeta40 and Abeta42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.
越来越多的证据表明，线粒体功能障碍是阿尔茨海默病（AD）发病机制的一个核心因素。AD 的最重要的危险因素是年龄增长，AD 的一个重要神经病理学相关性是淀粉样β肽（Abeta40 和 Abeta42）在大脑中的沉积。唐氏综合征（DS）老年患者也常出现类似 AD 的痴呆，但发病更早。我们已经表明，体细胞线粒体 DNA（mtDNA）控制区（CR）突变会随着年龄的增长在有丝分裂后组织中积累，包括大脑，并且 AD 患者大脑中的 mtDNA 突变水平明显升高。AD 大脑中升高的 mtDNA CR 突变与 mtDNA 拷贝数的减少和 mtDNA L 链转录水平的降低有关。我们现在表明，mtDNA CR 突变会随着对照大脑的年龄增长而增加；它们在 AD 和 DSAD 患者的大脑中明显升高；并且 DSAD 大脑中增加的 mtDNA CR 突变率与 mtDNA 拷贝数和 L 链转录物减少有关。在 AD 和 DSAD 患者的外周血 DNA 和淋巴母细胞 DNA 中也观察到 mtDNA CR 突变率增加，并且在 AD 和 DSAD 大脑和血细胞 DNA 中也观察到独特的体细胞 mtDNA 突变，通常具有高异质性水平。在衰老、DS 和 DSAD 中，mtDNA 突变水平与β-分泌酶活性呈正相关，mtDNA 拷贝数与不溶性 Abeta40 和 Abeta42 水平呈负相关。因此，mtDNA 改变可能是导致与年龄相关的痴呆症以及 AD 和 DSAD 中观察到的相关神经病理学变化的原因。
