Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits.
Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits.
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DOI：
10.1038/nn.3486
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发表时间：
2013-09
影响因子：
25
通讯作者：
Klann, Eric
中科院分区：
文献类型：
--
作者：
Ma, Tao;Trinh, Mimi A.;Wexler, Alyse J.;Bourbon, Clarisse;Gatti, Evelina;Pierre, Philippe;Cavener, Douglas R.;Klann, Eric
突触可塑性和长时记忆的表达需要新的蛋白质合成，而真核生物起始因子2α亚基（eIF 2 α）的磷酸化可抑制新蛋白质的合成。已有研究表明，阿尔茨海默病（Alzheimer's disease，AD）患者和AD模型小鼠脑内eIF 2 α磷酸化水平升高。因此，我们确定抑制eIF 2 α激酶是否可以减轻AD模型小鼠的突触可塑性和记忆缺陷。在APP/PS1 AD模型小鼠中，eIF 2 α激酶PERK的基因缺失阻止了eIF 2 α磷酸化的增强，以及蛋白质合成、突触可塑性和空间记忆的缺陷。类似地，另一种eIF 2 α激酶GCN 2的缺失防止了APP/PS1小鼠中显示的突触可塑性和空间记忆缺陷的损害。我们的研究结果表明，异常eIF 2 α磷酸化是一种新的分子机制，是AD相关的突触病理生理学和记忆功能障碍的基础，并表明PERK和GCN 2是治疗AD患者的潜在治疗靶点。
Expression of long-lasting synaptic plasticity and long-term memory requires new protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2α subunit (eIF2α). It was reported previously that eIF2α phosphorylation is elevated in the brains of Alzheimer’s disease (AD) patients and AD model mice. Therefore, we determined whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in AD model mice. The genetic deletion of the eIF2α kinase PERK prevented enhanced eIF2α phosphorylation, as well as deficits in protein synthesis, synaptic plasticity, and spatial memory in APP/PS1 AD model mice. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and spatial memory defects displayed in the APP/PS1 mice. Our findings implicate aberrant eIF2α phosphorylation as a novel molecular mechanism underlying AD-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for the treatment of individuals with AD.
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影响因子：
5.3
作者：
Banko, JL;Poulin, F;Klann, E
通讯作者：
Klann, E
影响因子：
16.2
作者：
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影响因子：
64.8
作者：
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影响因子：
5.3
作者：
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通讯作者：
Wek, RC
影响因子：
64.5
作者：
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通讯作者：
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