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Intraneuronal β-amyloid accumulation and apoplotic signals in Alzheimer's disease

阿尔茨海默病中神经元内 β-淀粉样蛋白的积累和细胞凋亡信号

基本信息

批准号：
14570902
负责人：
NUNOMURA Akihiko
金额：
$ 1.66万
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：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570902/
关键词：
Alzheimer's disease Apoptosis β-amyloid Hitogen-activated protein kinases Caspases Oxidative stress

项目摘要

Increasing evidence implicates oxidative stress and mitochondrial abnormalities in the pathogenesis of Alzheimer's disease(AD), which potentially cause apoptotic cell death. While the alterations in the metabolism of β-amyloid are considered to play major roles in AD, the relationship between intraneuronal β-amyloid accumulation and apoptotic signals remains to be elucidated.We used an in situ approach to identify intraneuronal β-amyloid accumulation, oxidalive damage, and apoptoltc signals in the hippocampus, papahippocampal gyrus and occipitoteraporal gyrus of postmortem brains of AD cases(n=10,age 60-87y). Immunocytochemically, up-stream signals in the apoptotic cascade, mitogen-activated protein kinases such as ERK,JNK/SAPK, and p38 were identified in the pyramidal neurons of these brain regions. Among subsequent signals, initiator caspases(caspases 8 and 9) appeared also in the pyramidal neurons. However, we failed to observe down-stream signals, effecter caspases(caspases 3,6,and 7), which might appear immediately before apoptotic cell death. Intraneuronal β-amyloid accumulation identified with an antibody against C-terminus of β-amyloid 1-42 showed more widespread distribution compared to any apoptotic signals investigated. Furthermore, oxidative damage to neuronal RNA identified with an antibody against oxidized nucleoside, 8-hydroxyguanosine showed more widespread distribution compared to the intraneuronal β-amyloid accumulation.These observations suggest temporal primacy of oxidative damage to intraneuronal β-amyloid accumulation and subsequent aclivation of apoptotic signals. The lack of signals of effecter caspases may indicate an abortive process of apoptosis in surviving neurons of AD.

越来越多的证据表明，氧化应激和线粒体异常在阿尔茨海默病（AD）的发病机制中可能导致细胞凋亡。虽然β-淀粉样蛋白代谢的改变被认为在AD中起主要作用，但神经元内β-淀粉样蛋白积聚与凋亡信号之间的关系仍有待阐明，我们使用原位方法鉴定AD病例（n=10，年龄60- 87岁）死后脑的海马、海马回和枕颞叶回中的神经元内β-淀粉样蛋白积聚、氧化损伤和凋亡信号。免疫细胞化学，上游信号的凋亡级联，丝裂原活化蛋白激酶，如ERK，JNK/SAPK，和p38被确定在这些大脑区域的锥体神经元。在随后的信号中，起始半胱天冬酶（半胱天冬酶8和9）也出现在锥体神经元中。然而，我们未能观察到下游信号，效应半胱天冬酶（半胱天冬酶3，6和7），这可能会出现之前立即凋亡细胞死亡。与研究的任何凋亡信号相比，用针对β-淀粉样蛋白1-42的C-末端的抗体鉴定的神经元内β-淀粉样蛋白积累显示出更广泛的分布。此外，与神经元内β-淀粉样蛋白积聚相比，用抗氧化核苷的抗体8-羟基鸟苷鉴定的神经元RNA的氧化损伤显示出更广泛的分布。AD存活神经元中效应caspase信号的缺乏可能提示凋亡过程的失败。