Suppression of the kinase for elongation factor 2 alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease.
Suppression of the kinase for elongation factor 2 alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2020.11.016
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发表时间：
2021-03
影响因子：
4.2
通讯作者：
Ma T
中科院分区：
文献类型：
--
作者：
Yang W;Zhou X;Ryazanov AG;Ma T
mRNA翻译（蛋白质合成）受损与阿尔茨海默病（AD）病理生理学有关。最近的研究表明，在AD相关的认知功能障碍中，真核细胞延伸因子2（eEF 2）的磷酸化水平增加。eEF 2（在Thr 56位点）被其唯一已知的激酶eEF 2K磷酸化导致一般蛋白质合成的抑制。AD被认为是一种以突触可塑性损伤为特征的“突触衰竭”疾病，包括长时程增强（LTP）和长时程抑制（LTD）。代谢型谷氨酸受体5依赖性LTD（mGluR-LTD）的缺乏表明与包括AD在内的各种神经系统疾病相关的认知综合征，但AD中mGluR-LTD失调的分子信号传导机制仍不清楚。在这个简短的交流中，我们报告了老年APP/PS1 AD模型小鼠中eEF 2K的遗传抑制可预防AD相关的海马mGluR-LTD缺陷。通过药理学方法，我们进一步观察到用小分子eEF 2K拮抗剂NH 125处理海马脑片可以挽救APP/PS 1小鼠中mGluR-LTD的损伤。总之，我们的研究结果表明，在AD相关的mGluR-LTD失败的延伸阶段异常蛋白质合成失调的关键作用，从而提供了深入了解AD和其他相关痴呆综合征的突触损伤的机制。
Impaired mRNA translation (protein synthesis) is linked to Alzheimer’s disease (AD) pathophysiology. Recent studies revealed a role of increased phosphorylation of eukaryotic elongation factor 2 (eEF2) in AD-associated cognitive deficits. Phosphorylation of eEF2 (at the Thr56 site) by its only known kinase eEF2K leads to inhibition of general protein synthesis. AD is considered as a disease of “synaptic failure” characterized by impairments of synaptic plasticity including long-term potentiation (LTP) and long-term depression (LTD). Deficiency of metabotropic glutamate receptor 5-dependent LTD (mGluR-LTD) is indicated in cognitive syndromes associated with various neurological disorders including AD, but the molecular signaling mechanisms underlying the mGluR-LTD dysregulation in AD remain unclear. In this brief communication, we report genetic repression of eEF2K in aged APP/PS1 AD model mice prevented AD-associated hippocampal mGluR-LTD deficits. Using pharmacological approach, we further observed that impairments of mGluR-LTD in APP/PS1 mice were rescued by treating hippocampal slices with a small molecule eEF2K antagonist NH125. Taken together, our findings suggest a critical role of abnormal protein synthesis dysregulation at the elongation phase in AD-associated mGluR-LTD failure, thus providing insights into mechanistic understanding of synaptic impairments in AD and other related dementia syndromes.
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影响因子：
--
作者：
Kenney, Justin W.;Moore, Claire E.;Proud, Christopher G.
通讯作者：
Proud, Christopher G.
影响因子：
56.9
作者：
Huber, KM;Kayser, MS;Bear, MF
通讯作者：
Bear, MF
影响因子：
25
作者：
Ma, Tao;Trinh, Mimi A.;Wexler, Alyse J.;Bourbon, Clarisse;Gatti, Evelina;Pierre, Philippe;Cavener, Douglas R.;Klann, Eric
通讯作者：
Klann, Eric
DOI：
10.1186/alzrt260
发表时间：
2014
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Ma T;Klann E
通讯作者：
Klann E
影响因子：
5.5
作者：
KATZ, B;MILEDI, R
通讯作者：
MILEDI, R