Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: Implications for Alzheimer's disease
Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: Implications for Alzheimer's disease
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DOI：
10.1523/jneurosci.5561-03.2004
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发表时间：
2004-03-10
影响因子：
5.3
通讯作者：
Takashima, A
中科院分区：
文献类型：
--
作者：
Planel, E;Miyasaka, T;Takashima, A
阿尔茨海默病（AD）的大脑含有由异常过度磷酸化的tau蛋白组成的神经元缠结（NFT）。在AD脑中已经报道了与NFT密度相关的脑葡萄糖代谢的区域性降低。假设葡萄糖代谢降低可能导致异常的tau蛋白过度磷酸化，我们通过饥饿或腹膜内注射胰岛素或脱氧葡萄糖诱导小鼠体内葡萄糖代谢的改变。我们发现，这些治疗导致异常的tau蛋白过度磷酸化，其模式与早期AD大脑中的模式相似，并且还导致体温过低。令人惊讶的是，tau蛋白的过度磷酸化可以追溯到低温对激酶和磷酸酶活性的不同影响。这些数据表明，异常tau蛋白过度磷酸化与通过体温过低改变的葡萄糖代谢有关。我们的研究结果表明，丝氨酸-苏氨酸蛋白磷酸酶2A在调节成人脑中的tau磷酸化中起主要作用，并为其在AD中异常tau过度磷酸化中的关键作用提供了体内证据。
Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein. Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine - threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.