Disruption of hnRNP A2-mediated RNA dynamics by amyloid-β drives MBP increase in Alzheimer’s disease
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. H...
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2025-08-01
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| Online Access: | https://doi.org/10.1007/s00018-025-05823-5 |
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| author | Adhara Gaminde-Blasco Rodrigo Senovilla-Ganzo Uxue Balantzategi Maialen Martinez-Preciado Estibaliz Capetillo-Zarate Fernando García-Moreno Carlos Matute Jimena Baleriola Elena Alberdi |
| author_facet | Adhara Gaminde-Blasco Rodrigo Senovilla-Ganzo Uxue Balantzategi Maialen Martinez-Preciado Estibaliz Capetillo-Zarate Fernando García-Moreno Carlos Matute Jimena Baleriola Elena Alberdi |
| author_sort | Adhara Gaminde-Blasco |
| collection | DOAJ |
| description | 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 Ca2+ 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 Ca2+ homeostasis critical for oligodendrocyte function. Graphical abstract |
| format | Article |
| id | doaj-art-d4014b2182484073bbfefa73c4369fb9 |
| institution | Kabale University |
| issn | 1420-9071 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Springer |
| record_format | Article |
| series | Cellular and Molecular Life Sciences |
| spelling | doaj-art-d4014b2182484073bbfefa73c4369fb92025-08-20T03:45:52ZengSpringerCellular and Molecular Life Sciences1420-90712025-08-0182112210.1007/s00018-025-05823-5Disruption of hnRNP A2-mediated RNA dynamics by amyloid-β drives MBP increase in Alzheimer’s diseaseAdhara Gaminde-Blasco0Rodrigo Senovilla-Ganzo1Uxue Balantzategi2Maialen Martinez-Preciado3Estibaliz Capetillo-Zarate4Fernando García-Moreno5Carlos Matute6Jimena Baleriola7Elena Alberdi8Department of Neuroscience, University of the Basque Country (UPV/EHU)Achucarro Basque Center for NeuroscienceDepartment of Neuroscience, University of the Basque Country (UPV/EHU)Department of Neuroscience, University of the Basque Country (UPV/EHU)Department of Neuroscience, University of the Basque Country (UPV/EHU)Department of Neuroscience, University of the Basque Country (UPV/EHU)Department of Neuroscience, University of the Basque Country (UPV/EHU)Achucarro Basque Center for NeuroscienceDepartment of Neuroscience, University of the Basque Country (UPV/EHU)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 Ca2+ 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 Ca2+ homeostasis critical for oligodendrocyte function. Graphical abstracthttps://doi.org/10.1007/s00018-025-05823-5OligodendrocytesMBPHnRNP A2Calcium homeostasisAmyloid-β peptideAlzheimer´s disease |
| spellingShingle | Adhara Gaminde-Blasco Rodrigo Senovilla-Ganzo Uxue Balantzategi Maialen Martinez-Preciado Estibaliz Capetillo-Zarate Fernando García-Moreno Carlos Matute Jimena Baleriola Elena Alberdi Disruption of hnRNP A2-mediated RNA dynamics by amyloid-β drives MBP increase in Alzheimer’s disease Cellular and Molecular Life Sciences Oligodendrocytes MBP HnRNP A2 Calcium homeostasis Amyloid-β peptide Alzheimer´s disease |
| title | Disruption of hnRNP A2-mediated RNA dynamics by amyloid-β drives MBP increase in Alzheimer’s disease |
| title_full | Disruption of hnRNP A2-mediated RNA dynamics by amyloid-β drives MBP increase in Alzheimer’s disease |
| title_fullStr | Disruption of hnRNP A2-mediated RNA dynamics by amyloid-β drives MBP increase in Alzheimer’s disease |
| title_full_unstemmed | Disruption of hnRNP A2-mediated RNA dynamics by amyloid-β drives MBP increase in Alzheimer’s disease |
| title_short | Disruption of hnRNP A2-mediated RNA dynamics by amyloid-β drives MBP increase in Alzheimer’s disease |
| title_sort | disruption of hnrnp a2 mediated rna dynamics by amyloid β drives mbp increase in alzheimer s disease |
| topic | Oligodendrocytes MBP HnRNP A2 Calcium homeostasis Amyloid-β peptide Alzheimer´s disease |
| url | https://doi.org/10.1007/s00018-025-05823-5 |
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