Tissue-nonspecific Alkaline Phosphatase Promotes the Neurotoxicity Effect of Extracellular Tau
Tissue-nonspecific Alkaline Phosphatase Promotes the Neurotoxicity Effect of Extracellular Tau
复制标题
DOI：
10.1074/jbc.m110.145003
复制
发表时间：
2010-10-15
影响因子：
4.8
通讯作者：
Avila, Jesus
中科院分区：
文献类型：
--
作者：
Diaz-Hernandez, Miguel;Gomez-Ramos, Alberto;Avila, Jesus
有确凿的证据表明，过度磷酸化的tau蛋白，存在于阿尔茨海默病患者脑中的细胞内神经元缠结的主要成分，在这种疾病的进展中起着关键作用。然而，最近有报道，细胞外未修饰的tau蛋白也可能通过激活M1和M3毒蕈碱受体诱导对海马神经元的神经毒性作用。在目前的工作中，我们显示了一个重要的组成部分，连接这两种效果，这是组织非特异性碱性磷酸酶（TNAP）。这种酶在中枢神经系统中含量丰富，主要用于控制磷酸化化合物的细胞外水平。一旦神经元死亡后释放，TNAP使过度磷酸化的tau蛋白去磷酸化。只有去磷酸化的tau蛋白作为毒蕈碱M1和M3受体的激动剂，引起强烈和持续的细胞内钙增加，最终触发神经元死亡。有趣的是，通过去磷酸化tau激活毒蕈碱受体增加了SH-SY 5 Y神经母细胞瘤细胞中TNAP的表达。与健康对照组相比，阿尔茨海默病患者的TNAP活性增加，蛋白质和转录水平增加。
There is solid evidence indicating that hyperphosphorylated tau protein, the main component of intracellular neurofibrillary tangles present in the brain of Alzheimer disease patients, plays a key role in progression of this disease. However, it has been recently reported that extracellular unmodified tau protein may also induce a neurotoxic effect on hippocampal neurons by activation of M1 and M3 muscarinic receptors. In the present work we show an essential component that links both effects, which is tissue-nonspecific alkaline phosphatase (TNAP). This enzyme is abundant in the central nervous system and is mainly required to keep control of extracellular levels of phosphorylated compounds. TNAP dephosphorylates the hyperphosphorylated tau protein once it is released upon neuronal death. Only the dephosphorylated tau protein behaves as an agonist of muscarinic M1 and M3 receptors, provoking a robust and sustained intracellular calcium increase finally triggering neuronal death. Interestingly, activation of muscarinic receptors by dephosphorylated tau increases the expression of TNAP in SH-SY5Y neuroblastoma cells. An increase in TNAP activity together with increases in protein and transcript levels were detected in Alzheimer disease patients when they were compared with healthy controls.