Alzheimer’s disease (AD) is characterised by Aβ and tau pathology as well as synaptic degeneration, which correlates best with cognitive impairment. Previous work suggested that this pathological complexity may result from changes in mRNA translation. Here, we studied whether mRNA translation and its underlying signalling are altered in an early model of AD, and whether modelling this deficiency in mice causes pathological features with ageing. Using an unbiased screen, we show that exposure of primary neurons to nanomolar amounts of Aβ increases FMRP-regulated protein synthesis. This selective regulation of mRNA translation is dependent on a signalling cascade involving MAPK-interacting kinase 1 (Mnk1) and the eukaryotic initiation factor 4E (eIF4E), and ultimately results in reduction of CYFIP2, an FMRP-binding protein. Modelling this CYFIP2 reduction in mice, we find age-dependent Aβ accumulation in the thalamus, development of tau pathology in entorhinal cortex and hippocampus, as well as gliosis and synapse loss in the hippocampus, together with deficits in memory formation. Therefore, we conclude that early stages of AD involve increased translation of specific CYFIP2/FMRP-regulated transcripts. Since reducing endogenous CYFIP2 expression is sufficient to cause key features of AD with ageing in mice, we suggest that prolonged activation of this pathway is a primary step toward AD pathology, highlighting a novel direction for therapeutic targeting.

阿尔茨海默病 (AD) 的特征是 Aβ 和 tau 病理学以及突触变性，这与认知障碍最相关。以前的工作表明，这种病理复杂性可能是由 mRNA 翻译的变化引起的。在这里，我们研究了早期 AD 模型中 mRNA 翻译及其潜在信号传导是否发生改变，以及在小鼠中建模这种缺陷是否会导致衰老的病理特征。使用无偏筛选，我们表明初级神经元暴露于纳摩尔量的 Aβ 会增加 FMRP 调节的蛋白质合成。这种对 mRNA 翻译的选择性调节依赖于涉及 MAPK 相互作用激酶 1 (Mnk1) 和真核起始因子 4E (eIF4E) 的信号级联反应，最终导致 FMRP 结合蛋白 CYFIP2 的减少。对小鼠的这种 CYFIP2 减少进行建模，我们发现丘脑中的年龄依赖性 Aβ 积累，内嗅皮层和海马中 tau 病理的发展，以及海马中的神经胶质增生和突触丧失，以及记忆形成的缺陷。因此，我们得出结论，AD 的早期阶段涉及特定 CYFIP2/FMRP 调节的转录物的翻译增加。由于降低内源性 CYFIP2 表达足以导致小鼠衰老导致 AD 的关键特征，我们认为延长该途径的激活是 AD 病理学的主要步骤，突出了治疗靶向的新方向。连同记忆形成的缺陷。因此，我们得出结论，AD 的早期阶段涉及特定 CYFIP2/FMRP 调节的转录物的翻译增加。由于降低内源性 CYFIP2 表达足以导致小鼠衰老导致 AD 的关键特征，我们认为延长该途径的激活是 AD 病理学的主要步骤，突出了治疗靶向的新方向。连同记忆形成的缺陷。因此，我们得出结论，AD 的早期阶段涉及特定 CYFIP2/FMRP 调节的转录物的翻译增加。由于降低内源性 CYFIP2 表达足以导致小鼠衰老导致 AD 的关键特征，我们认为延长该途径的激活是 AD 病理学的主要步骤，突出了治疗靶向的新方向。