2025/08/02 by Adhara Gaminde‐Blasco, Rodrigo Senovilla-Ganzo, Uxue Balantzategi +6 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Neuroscience · #RNA Research and Splicing #RNA regulation and disease #Nuclear Receptors and Signaling
paper · pdf · doi:10.1007/s00018-025-05823-5
openalex publication_date 2025/08/02 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
Abstract 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 2+ 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 2+ homeostasis critical for oligodendrocyte function. Graphical abstract