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

Abstract

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, Abeta oligomers, disrupt oligodendrocyte and myelin homeostasis, but a comprehensive global analysis of the mechanisms involved is lacking. Here, transcriptomic profiling of Abeta-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, Abeta-injected mouse hippocampi and Abeta-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. Abeta 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 Abeta oligomers disrupt RNA metabolism mechanisms crucial for oligodendrocyte myelination through dysregulation of hnRNP A2 and myelin protein levels, potentially affecting oligodendroglia Ca2+ homeostasis.