ASSESSING MTDNA VARIATION IN ALZHEIMER'S DISEASE

线粒体通过氧化磷酸化(OXPHOS)过程提供细胞的大部分能量。作为一种有毒的副产品，OXPHOS产生了我们细胞内产生的大部分内源性活性氧(ROS)。线粒体！据报道，AD患者的大脑和周围组织存在异常和OXPHOS缺陷。晚发性AD患者的母亲比父亲更有可能受到影响，已有几个轻微有害的mtDNA突变在AD患者中被报道，某些遗传的mtDNA谱系被发现对AD具有保护作用，并与延长寿命有关。此外，据报道，与年龄匹配的对照组相比，阿尔茨海默病患者的体细胞线粒体DNA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脑中mtDNA控制区突变显著增加。线粒体DNA L链启动子(PL)线粒体转录因子(MtTFA)结合位点的一个突变在65%的AD脑中存在，而在对照组中未发现。此外，一定 在某些患者的脑mtDNA中观察到高达80%的mtDNA CR突变，并观察到AD脑中mtDNA L链转录本和mtDNA拷贝数减少约50%，这两者都应导致AD患者部分OXPHOS缺陷。为了确定在AD患者中是否也系统地发现了在AD大脑中检测到的有害mtDNA控制区突变，我们建议检测AD患者的血细胞中的这些突变。以确定自然发生的 AD与其他长寿动物的线粒体DNA CR突变有关，我们建议寻找有害的线粒体DNA CR突变是痴呆的比格犬。为了确定抗氧化治疗是否会抑制mtDNA突变的发生，并改善mtDNA突变对大脑的生化影响，我们将检查正在接受抗氧化治疗的比格犬线粒体功能是否得到改善，以了解有害的mtDNA CR突变的水平。

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.