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首页> 外文期刊>The European Journal of Neuroscience >Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain.
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Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain.

机译：在阿尔茨海默氏病和唐氏综合症中增加MAP激酶活性，但在精神分裂症人脑中却没有。

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Introduction Abnormal phosphorylation of tau is a feature of Alzheimer's disease (AD), which develops prematurely in Down syndrome (DS) patients. Cognitive impairment is also recognized as a clinical characteristic of schizophrenia, which does not appear to be associated with tau-aggregate formation. Several kinases can phosphorylate tau in cell-free assays. Here we show increased activity of mitogen-activated protein kinases (MAPKs) (including ERK1/2, SAPKs and p38) in post mortem AD and DS brains, which could not be accounted for by expression changes. In contrast, glycogen synthase kinase-3 activity (GSK-3alphabeta) was reduced significantly. Examination of tau in AD and DS using antibodies selective for MAPK phosphorylation sites showed increased immunoreactivity. In addition, phosphorylation of S(199), reportedly a selective substrate for cyclin-dependent kinase-5 (cdk5) or GSK-3alphabeta was only observed in AD samples, which showed a concomitant increase in the expression of p25, the enhancing cofactor for cdk5 activity. However, in schizophrenia brain, MAPK-phosphorylated tau was unchanged compared to matched controls, despite similar expression levels to those in AD. The activities of the MAPKs and GSK-3alphabeta were also unchanged. These data demonstrate that in AD and DS, enhanced MAPK activity, which has an established role in regulating neuronal plasticity and survival, can account for irregular tau phosphorylation, and that the molecular processes involved in these neurodegenerative disorders are distinct from those in schizophrenia. These data also question the significance of GSK-3alphabeta, as much previous work carried out in vitro has placed this kinase as a favoured candidate for involvement in the pathological phosphorylation of tau.
机译：简介tau的磷酸化异常是阿尔茨海默氏病（AD）的特征，该疾病在唐氏综合症（DS）患者中过早发展。认知障碍也被认为是精神分裂症的临床特征，似乎与tau聚集体的形成无关。几种激酶可以在无细胞分析中磷酸化tau。在这里，我们显示了验尸AD和DS大脑中促分裂原活化蛋白激酶（MAPK）（包括ERK1 / 2，SAPKs和p38）的活性增加，这不能由表达变化来解释。相反，糖原合酶激酶3活性（GSK-3alphabeta）大大降低。使用对MAPK磷酸化位点有选择性的抗体对AD和DS中的tau进行检测显示免疫反应性增加。此外，仅在AD样品中观察到S（199）的磷酸化，据报道它是细胞周期蛋白依赖性激酶5（cdk5）或GSK-3alphabeta的选择性底物，这表明p25的表达随之增加，p25是增强型辅助因子。 cdk5活动。但是，在精神分裂症的大脑中，尽管与AD的表达水平相似，但与匹配的对照相比，MAPK磷酸化的tau却没有变化。 MAPKs和GSK-3alphabeta的活动也没有改变。这些数据表明，在AD和DS中，增强的MAPK活性在调节神经元可塑性和存活中具有确定的作用，可以解释不规则的tau磷酸化，并且这些神经退行性疾病涉及的分子过程不同于精神分裂症。这些数据也质疑了GSK-3alphabeta的重要性，因为在体外进行的许多先前工作已将该激酶作为参与tau病理磷酸化的首选候选物。

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