Restoring synaptic plasticity and memory in mouse models of Alzheimer's disease by PKR inhibition.
Restoring synaptic plasticity and memory in mouse models of Alzheimer's disease by PKR inhibition.
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DOI：
10.1186/s13041-017-0338-3
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发表时间：
2017-12-13
期刊：
影响因子：
3.6
通讯作者：
Lee YS
中科院分区：
文献类型：
--
作者：
Hwang KD;Bak MS;Kim SJ;Rhee S;Lee YS
阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，与认知和突触可塑性缺陷相关。虽然β淀粉样蛋白（Aβ）的积累和tau的过度磷酸化是病因的一部分，但AD可以由大量不同的基因突变和其他未知因素引起。考虑到AD的这种异质性，期望开发可以改善记忆的治疗策略，而不管个体原因如何。降低真核生物翻译起始因子2α（eIF 2 α）的磷酸化水平可增强未处理小鼠的长期记忆和突触可塑性。此外，在AD患者死后的脑中观察到eIF 2 α的过度磷酸化。因此，调节eIF 2 α磷酸化可能是通过靶向记忆增强机制恢复AD记忆的合理候选者。在这项研究中，我们检查了PKR抑制是否可以挽救两种不同AD小鼠模型中的突触和学习缺陷; 5XFAD转基因小鼠和Aβ1-42注射小鼠。我们发现PKR抑制剂（PKRi）的急性治疗可以恢复两种小鼠模型中的长时程记忆和长时程增强（LTP）缺陷，而不影响海马中的Aβ负荷。我们的研究结果证明了靶向记忆增强机制可以成为开发AD治疗的有效候选者的原则。本文的在线版本（10.1186/s13041-017-0338-3）包含补充材料，可供授权用户使用。
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with deficits in cognition and synaptic plasticity. While accumulation of amyloid β (Aβ) and hyper-phosphorylation of tau are parts of the etiology, AD can be caused by a large number of different genetic mutations and other unknown factors. Considering such a heterogeneous nature of AD, it would be desirable to develop treatment strategies that can improve memory irrespective of the individual causes. Reducing the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) was shown to enhance long-term memory and synaptic plasticity in naïve mice. Moreover, hyper-phosphorylation of eIF2α is observed in the brains of postmortem AD patients. Therefore, regulating eIF2α phosphorylation can be a plausible candidate for restoring memory in AD by targeting memory-enhancing mechanism. In this study, we examined whether PKR inhibition can rescue synaptic and learning deficits in two different AD mouse models; 5XFAD transgenic and Aβ1–42-injected mice. We found that the acute treatment of PKR inhibitor (PKRi) can restore the deficits in long-term memory and long-term potentiation (LTP) in both mouse models without affecting the Aβ load in the hippocampus. Our results prove the principle that targeting memory enhancing mechanisms can be a valid candidate for developing AD treatment. The online version of this article (10.1186/s13041-017-0338-3) contains supplementary material, which is available to authorized users.
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