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Transient upregulation of translational efficiency in prodromal and early symptomatic Tg2576 mice contributes to Aβ pathology.
Neurobiology of Disease ( IF 5.1 ) Pub Date : 2020-02-04 , DOI: 10.1016/j.nbd.2020.104787 Antonella Borreca 1 , Francesco Valeri 2 , Mariassunta De Luca 2 , Lysianne Ernst 3 , Arianna Russo 4 , Annalisa Nobili 5 , Alberto Cordella 5 , Veronica Corsetti 6 , Giuseppina Amadoro 7 , Nicola Biagio Mercuri 8 , Marcello D'Amelio 5 , Martine Ammassari-Teule 9
Neurobiology of Disease ( IF 5.1 ) Pub Date : 2020-02-04 , DOI: 10.1016/j.nbd.2020.104787 Antonella Borreca 1 , Francesco Valeri 2 , Mariassunta De Luca 2 , Lysianne Ernst 3 , Arianna Russo 4 , Annalisa Nobili 5 , Alberto Cordella 5 , Veronica Corsetti 6 , Giuseppina Amadoro 7 , Nicola Biagio Mercuri 8 , Marcello D'Amelio 5 , Martine Ammassari-Teule 9
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Tg2576 mice show high levels of human APP protein with Swedish Mutation during prodromal and early symptomatic stages. Interestingly, this is strictly associated with unbalanced expression of its two RNA binding proteins (RBPs) regulators, the Fragile-X Mental Retardation Protein (FMRP) and the heteronuclear Ribonucleoprotein C (hnRNP C). Whether an augmentation in overall translational efficiency also contributes to the elevation of APP levels at those early developmental stages is currently unknown. We investigated this possibility by performing a longitudinal polyribosome profiling analysis of APP mRNA and protein in total hippocampal extracts from Tg2576 mice. Results showed that protein polysomal signals were exclusively detected in pre-symptomatic (1 months) and early symptomatic (3 months) mutant mice. Differently, hAPP mRNA polysomal signals were detected at any age, but a peak of expression was found when mice were 3-month old. Consistent with an early but transient rise of translational efficiency, the phosphorylated form of the initial translation factor eIF2α (p-eIF2α) was reduced at pre-symptomatic and early symptomatic stages, whereas it was increased at the fully symptomatic stage. Pharmacological downregulation of overall translation in early symptomatic mutants was then found to reduce hippocampal levels of full length APP, Aβ species, BACE1 and Caspase-3, to rescue predominant LTD at hippocampal synapses, to revert dendritic spine loss and memory alterations, and to reinstate memory-induced c-fos activation. Altogether, our findings demonstrate that overall translation is upregulated in prodromal and early symptomatic Tg2576 mice, and that restoring proper translational control at the onset of AD-like symptoms blocks the emergence of the AD-like phenotype.
中文翻译：
前驱和早期有症状Tg2576小鼠的翻译效率的瞬时上调有助于Aβ病理。
Tg2576小鼠在前驱和症状早期阶段显示高水平的人类瑞典蛋白突变蛋白。有趣的是，这与它的两个RNA结合蛋白（RBPs）调节剂，脆性X智力低下蛋白（FMRP）和异核核糖核蛋白C（hnRNP C）的表达失衡密切相关。目前尚不清楚总体翻译效率的提高是否也有助于这些早期发育阶段APP水平的升高。我们通过对来自Tg2576小鼠的整个海马提取物中的APP mRNA和蛋白进行了纵向多核糖体分析来研究了这种可能性。结果显示，仅在有症状的前（1个月）和有症状的早期（3个月）突变小鼠中检测到蛋白质多体信号。不同的是 在任何年龄都可以检测到hAPP mRNA的多体体信号，但是当小鼠3个月大时发现了一个表达高峰。与早期但短暂的翻译效率提高相一致，在症状出现前和症状早期，磷酸化形式的初始翻译因子eIF2α（p-eIF2α）减少，而在完全症状阶段则增加。然后发现早期有症状突变体中整体翻译的药理学下调可降低海马全长APP，Aβ物种，BACE1和Caspase-3的海马水平，以挽救海马突触中的主要LTD，恢复树突棘的丧失和记忆力改变，并恢复原状。记忆诱导的c-fos激活。总而言之，我们的发现表明，在前驱和有症状的Tg2576小鼠中，整体翻译被上调，
更新日期：2020-02-04
中文翻译：
前驱和早期有症状Tg2576小鼠的翻译效率的瞬时上调有助于Aβ病理。
Tg2576小鼠在前驱和症状早期阶段显示高水平的人类瑞典蛋白突变蛋白。有趣的是，这与它的两个RNA结合蛋白（RBPs）调节剂，脆性X智力低下蛋白（FMRP）和异核核糖核蛋白C（hnRNP C）的表达失衡密切相关。目前尚不清楚总体翻译效率的提高是否也有助于这些早期发育阶段APP水平的升高。我们通过对来自Tg2576小鼠的整个海马提取物中的APP mRNA和蛋白进行了纵向多核糖体分析来研究了这种可能性。结果显示，仅在有症状的前（1个月）和有症状的早期（3个月）突变小鼠中检测到蛋白质多体信号。不同的是 在任何年龄都可以检测到hAPP mRNA的多体体信号，但是当小鼠3个月大时发现了一个表达高峰。与早期但短暂的翻译效率提高相一致，在症状出现前和症状早期，磷酸化形式的初始翻译因子eIF2α（p-eIF2α）减少，而在完全症状阶段则增加。然后发现早期有症状突变体中整体翻译的药理学下调可降低海马全长APP，Aβ物种，BACE1和Caspase-3的海马水平，以挽救海马突触中的主要LTD，恢复树突棘的丧失和记忆力改变，并恢复原状。记忆诱导的c-fos激活。总而言之，我们的发现表明，在前驱和有症状的Tg2576小鼠中，整体翻译被上调，
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