MITOCHONDRIAL DNA DELETIONS

最近的研究结果表明，大脑线粒体 DNA (mtDNA) 缺失 随着年龄的增长而增加，并且这些缺失具有区域性差异。 4977 大脑 mtDNA 中的碱基对缺失被发现随着年龄的增长而增加 神经节、黑质和额叶皮质。 相比之下，线粒体DNA很少 小脑中发现了缺失。 还有 7463 个碱基对 mtDNA 的水平 研究发现这些大脑区域的缺失随着年龄的增长而增加。 在 此外，大脑 mtDNA 密码子 331 的点突变似乎升高 在阿尔茨海默病中。 建议测量大脑 mtDNA 水平 额叶皮层 4977、7463 和密码子 331 点突变缺失， 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 缺失是可以测量的 采用定量聚合酶链式反应方法。 建议 比较正常和阿尔茨海默病大脑的数量和 线粒体DNA缺失的区域特异性。 将努力 相关病理结果（例如斑块计数、神经原纤维 缠结计数）与 mtDNA 缺失的程度和分布。 一个 线粒体DNA缺失的可能来源是氧化应激 炎症。 多种炎症因子刺激培养人体 星形细胞瘤细胞产生细胞因子白细胞介素-1 (IL-1) 和 白细胞介素-6 (IL-6)。 IL-6 促进异常神经元分化 凋亡。 IL-6和IL-1均促进阿尔茨海默病的合成 疾病β-淀粉样蛋白前体蛋白。 初步结果表明 用炎症剂处理的培养的星形细胞瘤细胞具有 超氧化物产量显着增加，线粒体 DNA 水平增加 删除。 建议通过以下方式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 mtDNA 缺失水平 对炎症刺激的反应以确定是否存在相关性 超氧化物产生与线粒体 DNA 缺失程度之间的关系。 这些 实验可能提供有关炎症作用的更多信息 阿尔茨海默病的病理生理学过程。

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.