Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer's Disease and Down Syndrome Dementia
Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer's Disease and Down Syndrome Dementia
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DOI：
10.3233/jad-2010-100351
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Wallace, Douglas C.
中科院分区：
文献类型：
--
作者：
Coskun, Pinar E.;Wyrembak, Joanne;Wallace, Douglas C.
越来越多的证据表明，线粒体功能障碍是阿尔茨海默病（AD）病因学的核心因素。阿尔茨海默病最重要的危险因素是高龄，阿尔茨海默病的一个重要的神经病理学相关因素是淀粉样β肽(A β（40)和A β(42)）在大脑中的沉积。ad样痴呆在老年唐氏综合症患者中也很常见，尽管发病时间要早得多。我们已经证明了体细胞线粒体！DNA （mtDNA）控制区（CR）突变在有丝分裂后组织（包括大脑）中随着年龄的增长而积累，并且在AD患者的大脑中mtDNA突变水平显著升高。AD大脑中mtDNA CR突变的升高与mtDNA拷贝数和mtDNA l链转录物水平的降低有关。我们现在发现，在对照大脑中，mtDNA CR突变随着年龄的增长而增加；它们在AD、DS和痴呆（DSAD）患者的大脑中显著升高；DSAD大脑中mtDNA CR突变率的增加与mtDNA拷贝数和l链转录物的减少有关。在AD和DSAD患者的外周血DNA和淋巴母细胞样细胞DNA中也可见到mtDNA CR突变率的增加，在AD和DSAD患者的脑组织和血细胞DNA中也可见到独特的体细胞mtDNA突变，通常呈高异质性水平。在衰老、DS和DSAD中，mtDNA突变水平与β -分泌酶活性正相关，mtDNA拷贝数与不溶性A β(40)和A β(42)水平负相关。因此，mtDNA的改变可能是AD和DSAD中与年龄相关的痴呆和相关神经病理改变的原因。
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 (A beta(40) and A beta(42)) 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 mitochondria! 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 A beta(40) and A beta(42) levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.