Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the β-amyloid peptide intracellularly in hippocampal and cortical neurons
Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the β-amyloid peptide intracellularly in hippocampal and cortical neurons
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DOI：
10.1016/j.neuroscience.2004.07.036
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发表时间：
2004-01-01
期刊：
影响因子：
3.3
通讯作者：
Cuello, AC
中科院分区：
文献类型：
--
作者：
Echeverria, V;Ducatenzeiler, A;Cuello, AC
体内细胞内Abeta蓄积的病理意义尚不完全清楚。为了解决这个问题，我们研究了表达阿尔茨海默病相关转基因基因的转基因大鼠，这些转基因大鼠在大脑和海马皮层内神经内积累Abeta，但不会形成细胞外淀粉样斑块。在这些大鼠中，神经元内Abeta的存在足以引起海马区细胞外调节激酶(ERK)2的磷酸化形式及其酶活性的上调，而其他可能的tau激酶如p38、糖原合成酶激酶3和细胞周期蛋白依赖性激酶5的活性或磷酸化状态没有变化。活性磷酸化ERK2的增加伴随着S396和S404 ERK2位点tau磷酸化水平的增加和CREB激酶p90RSK的磷酸化水平的降低。在水迷宫实验中，转基因雄性大鼠与对照仔鼠相比，表现出轻微的空间学习障碍。我们的结果表明，在没有斑块的情况下，Abeta肽在神经元内的积聚与tau-磷酸化级联反应的初始步骤、ERK2信号的改变和高级中枢神经系统功能的损害有关。(C)2004年IBRO。爱思唯尔有限公司出版。保留所有权利。
The pathological significance of intracellular Abeta accumulation in vivo is not yet fully understood. To address this, we have studied transgenic rats expressing Alzheimer's-related transgenes that accumulate Abeta intraneuronally in the cerebral and hippocampal cortices but do not develop extracellular amyloid plaques. In these rats, the presence of intraneuronal Abeta is sufficient to provoke up-regulation of the phosphorylated form of extracellular-regulated kinase (ERK) 2 and its enzymatic activity in the hippocampus while no changes were observed in the activity or phosphorylation status of other putative tau kinases such as p38, glycogen synthase kinase 3, and cycline-dependent kinase 5. The increase in active phospho-ERK2 was accompanied by increased levels of tau phosphorylation at S396 and S404 ERK2 sites and a decrease in the phosphorylation of the CREB kinase p90RSK. In a water maze paradigm, male transgenic rats displayed a mild spatial learning deficit relative to control littermates. Our results suggest that in the absence of plaques, intraneuronal accumulation of Abeta peptide correlates with the initial steps in the tau-phosphorylation cascade, alterations in ERK2 signaling and impairment of higher CNS functions in male rats. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.