AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo.
AMP-activated protein kinase modulates tau phosphorylation and tau pathology in vivo.
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DOI：
10.1038/srep26758
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发表时间：
2016-05-27
影响因子：
4.6
通讯作者：
Vingtdeux V
中科院分区：
文献类型：
--
作者：
Domise M;Didier S;Marinangeli C;Zhao H;Chandakkar P;Buée L;Viollet B;Davies P;Marambaud P;Vingtdeux V
神经元缠结（NFT）是通常称为tau蛋白病的神经退行性疾病的病理学标志。NFT由异常和过度磷酸化的tau蛋白的细胞内聚集引起。Tau的功能，包括微管动力学的调节，取决于其磷酸化状态。因此，tau蛋白磷酸化的任何变化都可能对突触可塑性和记忆产生重大影响。最近，已经证明，AMP活化蛋白激酶（AMPK）在阿尔茨海默病（AD）患者的脑中失调，其中它与缠结前和缠结承载神经元中的磷酸化tau共定位。此外，AMPK在体外被发现是一种tau激酶。在这里，我们发现，内源性AMPK激活小鼠原代神经元诱导增加tau磷酸化在多个网站，而AMPK抑制导致tau磷酸化的快速下降。我们进一步表明，AMPK小鼠缺乏一个催化α亚基显示减少内源性tau磷酸化。最后，我们发现AMPK缺乏减少了tau蛋白病的PS19小鼠模型中的tau蛋白病理学。这些结果表明AMPK调节小鼠原代神经元以及体内的tau磷酸化，因此表明AMPK可能是AD病理学发展中的关键参与者。
Neurofibrillary tangles (NFTs) are the pathological hallmark of neurodegenerative diseases commonly known as tauopathies. NFTs result from the intracellular aggregation of abnormally and hyperphosphorylated tau proteins. Tau functions, which include the regulation of microtubules dynamics, are dependent on its phosphorylation status. As a consequence, any changes in tau phosphorylation can have major impacts on synaptic plasticity and memory. Recently, it has been demonstrated that AMP-activated protein kinase (AMPK) was deregulated in the brain of Alzheimer’s disease (AD) patients where it co-localized with phosphorylated tau in pre-tangle and tangle-bearing neurons. Besides, it was found that AMPK was a tau kinase in vitro. Here, we find that endogenous AMPK activation in mouse primary neurons induced an increase of tau phosphorylation at multiple sites, whereas AMPK inhibition led to a rapid decrease of tau phosphorylation. We further show that AMPK mice deficient for one of the catalytic alpha subunits displayed reduced endogenous tau phosphorylation. Finally, we found that AMPK deficiency reduced tau pathology in the PS19 mouse model of tauopathy. These results show that AMPK regulates tau phosphorylation in mouse primary neurons as well as in vivo, and thus suggest that AMPK could be a key player in the development of AD pathology.