Disruption of hnRNP A2-mediated RNA dynamics by amyloid-β drives MBP increase in Alzheimer's disease

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Oligodendrocyte dysfunction and myelin degeneration contribute to cognitive decline in Alzheimer's disease (AD).
• Amyloid-β peptide (Aβ), a key player in AD, is known to disrupt oligodendrocyte and myelin homeostasis, but the underlying mechanisms are unclear.

Purpose of the Study:

• To investigate the mechanisms by which Aβ disrupts oligodendrocyte function and myelin homeostasis.
• To identify key molecular players involved in Aβ-induced oligodendrocyte dysfunction.

Main Methods:

• Transcriptomic profiling of Aβ-exposed oligodendrocytes.
• RNA-immunoprecipitation sequencing (RIP-seq) to identify hnRNP A2 interactome.
• Analysis of myelin protein synthesis and calcium influx in oligodendrocytes.

Main Results:

• Aβ exposure caused widespread gene expression changes in oligodendrocytes, particularly affecting RNA-related processes.
• hnRNP A2 was upregulated in AD patient samples, AD mouse models, and Aβ-treated oligodendrocytes.
• Aβ disrupted hnRNP A2's interaction with myelin component mRNAs (Mbp, Mobp), leading to impaired RNA metabolism, altered granule dynamics, enhanced MBP/MOBP synthesis, and reduced Ca2+ influx.

Conclusions:

• Aβ-induced dysregulation of hnRNP A2 impairs RNA metabolism and myelin protein synthesis in oligodendrocytes.
• These molecular disruptions alter intracellular Ca2+ homeostasis, critical for oligodendrocyte function and myelin integrity in AD.