The normal aging process is commonly associated with mild cognitive deficits including memory decline. Previous studies indicate a role of dysregulated messenger ribonucleic acid translation capacity in cognitive defects associated with aging and aging-related diseases, including hyperphosphorylation of eukaryotic elongation factor 2 (eEF2). Phosphorylation of eEF2 by the kinase eEF2K inhibits its activity, hindering general protein synthesis. Here, we sought to determine whether cognitive deficits in aged mice can be improved by genetically deleting eEF2K (eEF2K KO) and consequently reduction of eEF2 phosphorylation. We found that suppression of eEF2K prevented aging-related deficits in novel object recognition memory. Interestingly, deletion of eEF2K did not alter overall protein synthesis in the hippocampus. Ultrastructural analysis revealed increase size and larger active zone lengths of postsynaptic densities in the hippocampus of aged eEF2K KO mice. Biochemical assays showed hippocampal eIF2α hyperphosphorylation in aged eEF2K KO mice, indicating inhibition of translation initiation. Our findings may provide insight into mechanistic understanding and thus development of novel therapeutic strategies for aging-related cognitive decline.

中文翻译：

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抑制 eEF2 激酶可改善老年小鼠新物体识别记忆的缺陷。

正常的衰老过程通常与轻度认知缺陷有关，包括记忆力下降。先前的研究表明，信使核糖核酸翻译能力失调在与衰老和衰老相关疾病相关的认知缺陷中发挥作用，包括真核延伸因子 2 (eEF2) 的过度磷酸化。激酶 eEF2K 对 eEF2 的磷酸化会抑制其活性，从而阻碍一般的蛋白质合成。在这里，我们试图确定是否可以通过基因删除 eEF2K (eEF2K KO) 并因此减少 eEF2 磷酸化来改善老年小鼠的认知缺陷。我们发现抑制 eEF2K 可以防止新物体识别记忆中与衰老相关的缺陷。有趣的是，eEF2K 的缺失并未改变海马体中的整体蛋白质合成。超微结构分析显示老年 eEF2K KO 小鼠海马中突触后密度的大小和活动区长度增加。生化分析显示老年 eEF2K KO 小鼠的海马 eIF2α 过度磷酸化，表明翻译起始受到抑制。我们的研究结果可能会提供对机制理解的深入了解，从而为与衰老相关的认知衰退开发新的治疗策略。