Gaminde-Blasco Adhara, Senovilla-Ganzo Rodrigo, Balantzategi Uxue, Martinez-Preciado Maialen, Capetillo-Zarate Estibaliz, García-Moreno Fernando, Matute Carlos, Baleriola Jimena, Alberdi Elena
Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, 48940, Spain.
Achucarro Basque Center for Neuroscience, Leioa, 48940, Spain.
Cell Mol Life Sci. 2025 Aug 2;82(1):298. doi: 10.1007/s00018-025-05823-5.
Oligodendrocyte dysfunction, myelin degeneration, and white matter changes are critical events in the cognitive decline of Alzheimer's disease (AD). Amyloid-β peptide (Aβ), a hallmark of AD, disrupts oligodendrocyte and myelin homeostasis, through mechanisms that remain poorly understood. Here, transcriptomic profiling of Aβ-exposed oligodendrocytes revealed widespread gene expression changes, particularly in RNA-related processes. Among these, hnRNP A2, a key regulator of RNA transport and myelin protein regulation, was aberrantly upregulated in hippocampal oligodendrocytess from AD patients with high Aβ levels, from AD mouse models, and in Aβ-treated oligodendrocytes. RNA-immunoprecipitation sequencing of the hnRNP A2 interactome revealed Aβ-induced changes in mRNA interactions, particularly enriched binding to Mbp and Mobp, indicating impaired RNA metabolism of myelin components. Furthermore, Aβ, through hnRNP A2 disruption, increased the number, cargo and dynamics of Mbp- and Mobp-containing granules, enhanced MBP and MOBP synthesis, and decreased oligodendroglial voltage-gated Ca influx in an MBP-dependent manner. These findings suggest that Aβ-induced dysregulation of hnRNP A2 impairs RNA metabolism and myelin protein synthesis, altering the intracellular Ca homeostasis critical for oligodendrocyte function.
少突胶质细胞功能障碍、髓鞘变性和白质变化是阿尔茨海默病（AD）认知衰退中的关键事件。淀粉样β肽（Aβ）是AD的一个标志，它通过尚不清楚的机制破坏少突胶质细胞和髓鞘的稳态。在这里，对暴露于Aβ的少突胶质细胞进行转录组分析揭示了广泛的基因表达变化，特别是在与RNA相关的过程中。其中，hnRNP A2是RNA运输和髓鞘蛋白调节的关键调节因子，在Aβ水平高的AD患者的海马少突胶质细胞、AD小鼠模型以及Aβ处理的少突胶质细胞中异常上调。对hnRNP A2相互作用组进行RNA免疫沉淀测序发现，Aβ诱导了mRNA相互作用的变化，特别是与Mbp和Mobp的结合增加，这表明髓鞘成分的RNA代谢受损。此外，Aβ通过破坏hnRNP A2，增加了含Mbp和Mobp颗粒的数量、货物和动态，增强了MBP和MOBP的合成，并以MBP依赖的方式减少了少突胶质细胞电压门控钙内流。这些发现表明，Aβ诱导的hnRNP A2失调损害了RNA代谢和髓鞘蛋白合成，改变了对少突胶质细胞功能至关重要的细胞内钙稳态。
