MITOCHONDRIAL DNA DELETIONS

最近的研究结果表明，脑线粒体DNA（mtDNA）缺失 且这些缺失是区域性可变。 A4977 脑线粒体DNA碱基对缺失的基础研究发现，随着年龄的增长， 神经节、黑质和额叶皮质。 与此相反， 在小脑中发现缺失。 7463个碱基对的线粒体DNA 在这些大脑区域中，发现缺失随着年龄的增长而增加。 在 此外，脑线粒体DNA密码子331的点突变似乎升高， 老年痴呆症 有人建议测量大脑mtDNA的水平， 额叶皮层缺失4977、7463和密码子331点突变， 年龄匹配的大脑中的内侧颞叶皮层、壳核和小脑 非痴呆对照受试者和阿尔茨海默病患者。 初步结果表明，这些mtDNA缺失可以测量， 使用定量聚合酶链反应方法。 提出要 比较正常和阿尔茨海默病的大脑的数量和 mtDNA缺失的区域特异性。 将试图 相关病理学发现（例如斑块计数、神经病理学 缠结计数）与mtDNA缺失的程度和分布。 一 mtDNA缺失的可能来源是氧化应激， 炎症 多种炎性因子刺激培养的人类 星形细胞瘤细胞产生细胞因子白细胞介素-1（IL-1）， 白细胞介素-6（IL-6）。 IL-6促进异常神经元分化， 细胞凋亡 IL-6和IL-1都能促进阿尔茨海默氏症的合成， 淀粉样前体蛋白。 初步结果表明 用炎症剂处理的培养的星形细胞瘤细胞既具有 超氧化物生成显著增加，线粒体DNA水平增加 删除。 建议通过以下方法测量超氧化物的产生 培养的星形细胞瘤和神经元细胞，以及 以确定是否存在相关性 超氧化物的产生和线粒体DNA缺失的程度之间的关系。 这些 实验可以提供更多的信息，炎症的作用， 阿尔茨海默病的病理生理过程。

Recent results indicate that brain mitochondrial DNA (mtDNA) deletions increase with age and that these deletions are regionally variable. A 4977 basepair deletion in brain mtDNA was found to increase with age in basal ganglia, substantia nigra, and frontal cortex. In contrast few mtDNA deletions were found in cerebellum. Also levels of a 7463 basepair mtDNA deletion were found to increase with age in these brain regions. In addition, point mutations in codon 331 of brain mtDNA appear to be elevated in Alzheimer's disease. It is proposed to measure levels of brain mtDNA deletions 4977, 7463, and codon 331 point mutation in frontal cortex, medial temporal cortex, putamen, and cerebellum in brains from age-matched non-demented control subjects and Alzheimer's disease patients. Preliminary results indicate that these mtDNA deletions can be measured using a quantitative polymerase chain reaction method. It is proposed to compare normal and Alzheimer's disease brain for both the amount and regional specificity of mtDNA deletions. Attempts will be made to correlated pathological findings (e.g. plaque counts, neurofibrillary tangle counts) with the extent and distribution of mtDNA deletions. A possible source of mtDNA deletions is oxidative stress arising from inflammation. A variety of inflammatory agents stimulate cultured human astrocytoma cells to produce the cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6). IL-6 promotes aberrant neuronal differentiation and aptosis. Both IL-6 and IL-1 promote the synthesis of the Alzheimer's disease beta-amyloid precursor protein. Preliminary results suggest that cultured astrcytoma cells treated with inflammatory agents have both a marked increase in superoxide production and increased levels of mtDNA deletions. It is proposed to measure both superoxide production by cultured astrocytoma and neuronal cells, and levels of mtDNA deletions in response to inflammatory stimuli to determine if there are correlations between superoxide production and the extent of mtDNA deletions. These experiments may provide additional information on the role of inflammatory processes in the pathophysiology of Alzheimer's disease.