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

评估人类阿尔茨海默病的 MTDNA 变异和犬模型

• 批准号: 7848206
• 负责人: DOUGLAS WALLACE
• 金额: $ 22.22万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7848206
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Animal Model; Animals; Antioxidants; Apoptosis; Binding Sites; Biochemical; Biological; Blood; Blood Cells; Brain; California; Canis familiaris; Cell physiology; Cells; Cognitive; DNA copy number; Defect; Dementia; Development; Diet; Disease; Energy-Generating Resources; Etiology; Fathers; Gene Rearrangement; Grant; Haplogroup; Human; Impaired cognition; Inherited; Late Onset Alzheimer Disease; Life; Longevity; Mitochondria; Mitochondrial DNA; Molecular; Mothers; Mutation; Oxidative Phosphorylation; Oxidative Phosphorylation Deficiency; Patients; Performance; Peripheral; Permeability; Play; Process; Production; Reactive Oxygen Species; Relative (related person); Reporting; Research; Research Personnel; Role; Testing; Tissues; Transcript; Universities; Variant; antioxidant therapy; brain cell; cofactor; density; enzyme activity; improved; mitochondrial DNA mutation; mutant; peripheral blood; programs; promoter; research study; transcription factor

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.

线粒体通过氧化磷酸化（OXPHOS）过程提供我们细胞的大部分能量。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！已经报道了AD患者的脑和外周组织的异常和OXPHOS缺陷。晚发性AD患者更可能有一个受影响的母亲比父亲，几个轻度有害的mtDNA突变已报告在AD患者和某些遗传mtDNA谱系已被发现对AD的保护，并与寿命延长。此外，据报道，体细胞mtDNA重排突变在AD脑中相对于年龄匹配的对照增加了15倍。最近，我们发现，线粒体DNA控制区突变显着升高，在AD脑相对于年龄匹配的控制。在线粒体DNA L-链启动子（PL）的线粒体转录因子（mtTFA）结合位点的一个突变被证明是存在于65%的AD大脑，但没有控制。此外，某些 在某些患者中，观察到高达80%的脑mtDNA中存在mtDNA CR突变，并且观察到AD脑中mtDNA L-链转录物和mtDNA拷贝数减少约50%，这两者都应导致AD中的部分OXPHOS缺陷。为了确定在AD脑中检测到的有害mtDNA控制区突变是否也在AD患者中全身发现，我们建议测试AD患者的血细胞中的这些突变。以确定是否自然发生 在其他长寿动物中，AD与mtDNA CR突变相关，我们建议在痴呆比格犬中寻找有害的mtDNA CR突变。为了确定抗氧化剂治疗是否会抑制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剂治疗的比格犬的线粒体功能是否改善，以了解有害的mtDNA CR突变水平。