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首页> 外文期刊>Molecular and Cellular Biology >Increased tau Phosphorylation on Mitogen-Activated Protein Kinase Consensus Sites and Cognitive Decline in Transgenic Models for Alzheimer's Disease and FTDP-17: Evidence for Distinct Molecular Processes Underlying tau Abnormalities
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Increased tau Phosphorylation on Mitogen-Activated Protein Kinase Consensus Sites and Cognitive Decline in Transgenic Models for Alzheimer's Disease and FTDP-17: Evidence for Distinct Molecular Processes Underlying tau Abnormalities

机译：在阿尔茨海默氏病和FTDP-17转基因模型中，丝裂素激活的蛋白激酶共识位点上的tau磷酸化增加和认知能力下降：tau异常背后不同分子过程的证据

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Abnormal tau phosphorylation occurs in several neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here, we compare mechanisms of tau phosphorylation in mouse models of FTDP-17 and AD. Mice expressing a mutated form of human tau associated with FTDP-17 (tauV337M) showed age-related increases in exogenous tau phosphorylation in the absence of increased activation status of a number of kinases known to phosphorylate tau in vitro. In a “combined” model, expressing both tauV337M and the familial amyloid precursor protein AD mutation APPV717I in a CT100 fragment, age-dependent tau phosphorylation occurred at the same sites and was significantly augmented compared to “single” tauV337M mice. These effects were concomitant with increased activation status of mitogen-activated protein kinase (MAPK) family members (extracellular regulated kinases 1 and 2, p38, and c-Jun NH2-terminal kinase) but not glycogen synthase kinase-3αβ or cyclin-dependent kinase 5. The increase in MAPK activation was a discrete effect of APPV717I-CT100 transgene expression as near identical changes were observed in single APPV717I-CT100 mice. Age-dependent deficits in memory were also associated with tauV337M and APPV717I-CT100 expression. The data reveal distinct routes to abnormal tau phosphorylation in models of AD and FTDP-17 and suggest that in AD, tau irregularities may be linked to processing of APP C-terminal fragments via specific effects on MAPK activation status.
机译：tau蛋白磷酸化异常发生在几种神经退行性疾病中，包括阿尔茨海默氏病（AD）和额颞叶痴呆，伴有与17号染色​​体相关的帕金森氏症（FTDP-17）。在这里，我们比较FTDP-17和AD小鼠模型中tau磷酸化的机制。表达与FTDP-17相关的人tau突变形式（tau V337M ）的小鼠显示出与年龄相关的外源性tau磷酸化增加，而没有已知许多能够使tau磷酸化的激酶的活化状态增加。体外。在“组合”模型中，在CT100片段中同时表达tau V337M 和家族淀粉样蛋白前体蛋白AD突变APP V717I ，年龄依赖性tau磷酸化发生在同一位点与“单” tau V337M 小鼠相比，其显着增强。这些作用与丝裂原活化蛋白激酶（MAPK）家族成员（细胞外调节激酶1和2，p38和c-Jun NH 2 末端激酶）的活化状态增加有关，而与糖原合酶无关激酶3αβ或细胞周期蛋白依赖性激酶5。MAPK激活的增加是APP V717I -CT100转基因表达的离散作用，因为单个APP V717I 观察到几乎相同的变化-CT100小鼠。年龄依赖性的记忆缺陷也与tau V337M 和APP V717I -CT100表达有关。数据揭示了在AD和FTDP-17模型中异常tau磷酸化的独特途径，并暗示在AD中，tau异常可能通过对MAPK激活状态的特定影响与APP C末端片段的加工有关。

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