4-hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau
4-hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau
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DOI：
10.1097/00001756-199707070-00036
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发表时间：
1997-07-07
期刊：
影响因子：
1.7
通讯作者：
Uchida, K
中科院分区：
文献类型：
--
作者：
Mattson, MP;Fu, WM;Uchida, K
在阿尔茨海默病 (AD) 中，退化神经元中的微管相关蛋白 tau 过度磷酸化，但磷酸化增加的机制尚不清楚。最近的研究结果表明，氧化应激，特别是膜脂过氧化，有助于 AD 的神经退行性过程。我们现在报道，将培养的大鼠海马神经元暴露于 4-羟基壬烯醛 (HNE)（一种膜脂过氧化的醛产物）后，tau 蛋白对去磷酸化具有抵抗力。使用磷酸化敏感 tau 抗体进行的免疫细胞化学和蛋白质印迹分析表明，HNE 处理会导致 tau 磷酸化基础水平适度增加，并防止用磷酸酶抑制剂冈田酸预处理的神经元中碱性磷酸酶导致 tau 去磷酸化。抗 HNE 抗体的研究表明，HNE 直接与 tau 结合，并且 HNE 免疫反应性定位于细胞体和轴突（含有 tau 的细胞区室）。这些数据表明 HNE 在 AD 中 tau 磷酸化改变和神经原纤维变性中发挥作用。
IN Alzheimer's disease (AD) the microtubule-associated protein tau is excessively phosphorylated in degenerating neurons, but the mechanisms underlying the increased phosphorylation are unknown. Recent findings suggest that oxidative stress, and membrane lipid peroxidation in particular, contributes to the neurodegenerative process in AD. We now report that following exposure of cultured rat hippocampal neurons to 4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, tau is resistant to dephosphorylation. Immunocytochemical and Western blot analyses using phosphorylation-sensitive tau antibodies showed that HNE treatment causes a moderate increase in basal levels of tau phosphorylation, and prevents tau dephosphorylation by alkaline phosphatase in neurons pretreated with the phosphatase inhibitor okadaic acid. Studies with anti-HNE antibodies showed that HNE binds directly to tau, and that HNE immunoreactivity localizes to cell bodies and axons, cell compartments that contain tau. These data suggest a role for HNE in altered tau phosphorylation and neurofibrillary degeneration in AD.