MITOCHONDRIAL DNA DELETIONS

线粒体 DNA 缺失

• 批准号: 5204483
• 负责人: LARRY ALTSTIEL
• 金额: --
• 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/5204483
• 关键词: Alzheimer's disease; aging; astrocytoma; cerebellum; cytokine; frontal lobe /cortex; gene deletion mutation; glia; human tissue; hydrogen peroxide; mitochondrial DNA; neuritic plaques; neurofibrillary tangles; neuroimmunomodulation; neuropharmacology; oxidative stress; point mutation; polymerase chain reaction; putamen; superoxides; temporal lobe /cortex; tissue /cell culture

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.

最近的研究结果表明，脑线粒体DNA （mtDNA）缺失