Amyloid-β increases MBP and MOBP translation in oligodendrocytes through dysregulation of hnRNP A2-dependent RNA dynamics

Oligodendrocyte dysfunction, myelin degeneration, and white matter structural alterations are critical events in Alzheimer's disease (AD) that contribute to cognitive decline. A key hallmark of AD, Aβ oligomers, disrupt oligodendrocyte and myelin homeostasis, but a comprehensive global analysis of the mechanisms involved is lacking. Here, transcriptomic profiling of Aβ-exposed oligodendrocytes revealed widespread gene expression changes, particularly affecting pathways related to RNA localisation. Among the genes identified, we focused on Hnrnpa2/b1, the gene encoding the hnRNP A2 protein, which is essential for RNA transport and translation of myelin proteins. We confirmed aberrant upregulation of hnRNP A2 in hippocampal oligodendrocytes from post-mortem human brains of early-stage AD patients, Aβ-injected mouse hippocampi and Aβ-treated disrupting cells in vitro. RIP-seq analysis of the hnRNP A2 interactome revealed attenuated interactions with Hnrnpk and Hnrnpa2/b1, while interactions with Mbp and Mobp were enriched, suggesting changes in RNA metabolism of molecules associated with mRNA transport of myelin proteins. Aβ increased the total number and dynamics of mRNA-containing granules, facilitating local translation of the myelin proteins MBP and MOBP and attenuating Ca2+ signalling. These findings suggest that Aβ oligomers disrupt RNA metabolism mechanisms crucial for oligodendrocyte myelination through dysregulation of hnRNP A2 and myelin protein levels, potentially affecting oligodendroglia Ca2+ homeostasis.少突胶质细胞（Oligodendrocyte）功能障碍、髓鞘变性以及白质结构改变是阿尔茨海默病（AD）中导致认知衰退的关键事件。β淀粉样蛋白寡聚体（Aβ oligomers）作为AD的核心标志性病理特征，会破坏少突胶质细胞与髓鞘稳态，但目前仍缺乏对其相关机制的全面全局分析。本研究对暴露于Aβ的少突胶质细胞开展转录组分析（transcriptomic profiling），发现广泛的基因表达变化，尤其影响与RNA定位（RNA localisation）相关的通路。在筛选得到的差异基因中，我们聚焦于Hnrnpa2/b1基因——该基因编码异质性细胞核核糖蛋白A2（hnRNP A2），后者对于RNA转运及髓鞘蛋白的翻译至关重要。我们证实，在早期AD患者死后人脑的海马体少突胶质细胞、Aβ注射小鼠的海马体以及体外Aβ处理的少突胶质细胞中，hnRNP A2均存在异常上调。对hnRNP A2相互作用组的RNA免疫沉淀测序（RIP-seq）分析显示，其与Hnrnpk以及Hnrnpa2/b1的相互作用减弱，而与髓鞘碱性蛋白（MBP）、髓鞘相关少突胶质细胞碱性蛋白（MOBP）的相互作用则显著富集，这提示髓鞘蛋白mRNA转运相关分子的RNA代谢发生了改变。Aβ可增加含mRNA的颗粒的总数与动力学特性，促进髓鞘蛋白MBP与MOBP的局部翻译，并减弱钙离子（Ca²+）信号通路。本研究结果表明，β淀粉样蛋白寡聚体通过失调hnRNP A2及髓鞘蛋白水平，破坏了少突胶质细胞髓鞘形成所必需的RNA代谢机制，或可影响少突胶质细胞的钙离子稳态。