ASSESSING MTDNA VARIATION IN ALZHEIMER'S DISEASE IN MAN AND A CANINE MODEL

线粒体通过氧化磷酸化（OXPHOS）过程为我们的细胞提供大部分能量。作为一种有毒的副产物，OXPHOS产生了我们细胞内大部分的内源性活性氧（ROS）。线粒体!据报道，阿尔茨海默病患者的大脑和外周组织存在异常和OXPHOS缺陷。迟发性阿尔茨海默氏症患者的母亲比父亲更有可能受到影响，一些轻度有害的mtDNA突变已在阿尔茨海默氏症患者中被报道，某些遗传mtDNA谱系已被发现可以预防阿尔茨海默氏症，并与延长寿命有关。此外，据报道，与年龄匹配的对照组相比，阿尔茨海默病大脑中体细胞mtDNA重排突变增加了15倍。最近，我们发现与年龄匹配的对照组相比，AD大脑中mtDNA控制区突变明显升高。65%的阿尔茨海默氏症患者大脑中存在mtDNA l链启动子（PL）线粒体转录因子（mtTFA）结合位点的一个突变，但没有对照组。此外,某些

The mitochondria provide most of the energy of our cells by the process of oxidative phosphorylation (OXPHOS). As a toxic by-product, OXPHOS generates most of the endogenous reactive oxygen species (ROS) generated within our cells. Mitochondria! abnormalities and OXPHOS deficiencies have reported for the brains and peripheral tissues of AD patients. Late-onset AD patients are more likely to have an affected mother than father, several mildly deleterious mtDNA mutations have been reported in AD patients and certain inherited mtDNA lineages have been found to be protected against AD and associated with increased longevity. Moreover, somatic mtDNA rearrangement mutations have been reported to be increased 15 fold in AD brains relative to age-matched controls. Recently, we have discovered that mtDNA control region mutations are markedly elevated in AD brains relative to age-matched controls. One mutation in the mtDNA L-strand promoter (PL) mitochondrial transcription factor (mtTFA) binding site was shown to be present in 65% of AD brains but in no controls. Furthermore, certain mtDNA CR mutations were observed to be present in up to 80% of brain mtDNAs in certain patients, and AD brains were observed to have an approximately 50% reduction in mtDNA L-strand transcripts and in the mtDNA copy number, both of which should result in partial OXPHOS deficiency in AD. To determine if the deleterious mtDNA control region mutations detected in AD brains are also found systemically in AD patients, we propose to test the blood cells of AD patients for these mutations. To determine if naturally-occurring AD is associated with mtDNA CR mutations in other long-lived animals, we propose to look for deleterious mtDNA CR mutations is demented beagle dogs. To determine if anti-oxidant treatments would inhibit the occurrence of the mtDNA mutations and ameliorate the biochemical effects of the mtDNA mutations on the brain, we will examine beagles for improved mitochondrial function that are on anti-oxidant therapy for the level of deleterious the mtDNA CR mutations.