IMMUNOCYTOCHEMICAL STUDIES ON OXIDATIVE DAMAGE IN THE BRAINS OF ALZHEIMER'S DISEASE

阿尔茨海默病大脑氧化损伤的免疫细胞化学研究

• 批准号: 12670918
• 负责人: NUNOMURA Akihiko
• 金额: $ 2.24万
• 依托单位: ASAHIKAWA MEDICAL COLLEGE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670918/
• 关键词: Alzheimer's disease; Amyloyd-β; Down's syndrome; 8-hydroxyguanosine; Nitrotyrosine; Oxidative damage; Presenilin; RNA; Nitric oxide; Oxidative stress

Increasing evidence implicates oxidative stress in the aging process of the brain as well as in Alzheimer's disease (AD) and Down's syndrome (DS). We used an in situ approach to identify the oxidized nucleoside, 8-hydroxyguanosine (8OHG; the 1F7 antibody) in the cerebral cortex of familial AD with presenflin-1 mutations (n=12, age 47-81 y), sporadic AD (n = 22, 57-93 y), DS (n=22, 0.3-64 y), and non-demented patients (n=40, 0.3-86 y). Relative intensity measurements of 80HG immunoreactivity (Q500IW-EX, Leica) showed there was an age-related increase of neuronal 8OHG in non-demented patients. In sporadic AD and DS, but not in familial AD, neuronal 8OHG significantly increased compared to age-matched controls. Interestingly, significant 8OHG elevation temporally precedes the significant increase of amyloid β deposition in DS, and the levels of 8OHG inversely correlated with % amyloid β burden in sporadic AD and DS. Neuronal nucleic acid oxidation is an age-related event as well as an upstream event in the pathological cascade of sporadic AD and DS. Deposition of Aβmay be related to a compensatory response to sustained oxidative stress in AD and DS.

越来越多的证据表明，氧化应激与大脑的衰老过程以及阿尔茨海默病（AD）和唐氏综合征（DS）有关。我们使用原位方法鉴定了具有presenflin-1突变的家族性AD（n=12，年龄47-81岁）、散发性AD（n = 22，57-93岁）、DS（n = 22，0.3-64岁）和非痴呆患者（n=40，0.3-86岁）的大脑皮层中的氧化核苷、8-羟基鸟苷（8 OHG; 1F 7抗体）。80 HG免疫反应性的相对强度测量（Q500 IW-EX，Leica）显示在非痴呆患者中神经元80 HG存在年龄相关的增加。在散发性AD和DS中，而不是在家族性AD中，与年龄匹配的对照组相比，神经元8 OHG显著增加。有趣的是，在DS中，8 OHG显著升高在时间上先于淀粉样蛋白β沉积的显著增加，并且在散发性AD和DS中，8 OHG水平与淀粉样蛋白β负荷%呈负相关。神经元核酸氧化是年龄相关事件，也是散发性AD和DS病理级联反应的上游事件。Aβ沉积可能与AD和DS中对持续氧化应激的代偿反应有关。

项目成果

A.Nunomura: "Increasing amyloid β 42 deposition is associated with decreasing neuronal RNA oxidation in Down's syndrome and familial Alzheimer's disease"Brain Pathology. 10. 783 (2000)

A.Nunomura：“β 42 淀粉样蛋白沉积的增加与唐氏综合症和家族性阿尔茨海默病中神经元 RNA 氧化的减少有关”《脑病理学》10. 783 (2000)。

布村 明彦: "RNAの酸化とアルツハイマー病"Dementia Japan. 14. 39-45 (2000)

Akihiko Numura：“RNA 氧化和阿尔茨海默病”日本痴呆症 14. 39-45 (2000)。

A.Nunomura: "Neuronal oxidative stress precedes amyloid-β deposition in Down syndrome"Journal of Neuropatholgy and Experimental Neurology. 21. 3017-3023 (2001)

A. Nunomura：“唐氏综合症中神经氧化应激先于淀粉样蛋白-β 沉积”《神经病理学和实验神经病学杂志》21. 3017-3023 (2001)。

布村 明彦: "RNAの酸化とアルツハイマー病"Dementia Japan. 14・1. 39-45 (2000)

Akihiko Nunomura：“RNA氧化和阿尔茨海默病”日本痴呆症14・1（2000年）。

A.Nunomura: "Neuronal oxidative stress precedes amyloid-β deposition in Down syndrome"Journal of Neuropathology and Experimental Neurology. 59・11. 1011-1017 (2000)

A. Nunomura：“唐氏综合症中神经氧化应激先于β淀粉样蛋白沉积”《神经病理学和实验神经病学杂志》59・11（2000）。