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N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer’s disease

Summary

This research reveals how an abnormal RNA molecule called circRIMS2 contributes to Alzheimer’s disease by damaging brain synapses and impairing memory. Scientists found that circRIMS2 levels are elevated through a chemical modification called m6A methylation, and this causes a cascade of events leading to the destruction of important proteins needed for brain communication. The study shows that blocking this damaging pathway using a specially designed peptide can restore memory and synaptic function in Alzheimer’s disease models, offering hope for new therapeutic approaches.

Background

Synaptic degeneration occurs early in Alzheimer’s disease and correlates with cognitive decline. Circular RNAs are abundantly enriched in neural tissues and dysregulated in AD, but their direct relationship to synaptic impairment remains unclear.

Objective

To identify dysregulated circRNAs in early-stage AD and elucidate the mechanisms linking circRNA dysregulation to synaptic impairment through investigation of the circRIMS2/miR-3968 pathway.

Results

circRIMS2 was significantly upregulated via METTL3-dependent N6-methyladenosine modification in APP/PS1 mice. CircRIMS2 acts as a miRNA sponge for miR-3968, leading to UBE2K upregulation and GluN2B ubiquitination at K1082, causing synaptic and memory impairments. Blocking this pathway through peptide intervention or pathway component silencing rescued synaptic dysfunction.

Conclusion

m6A-modified circRIMS2 mediates synaptic and memory impairments in AD by activating UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD intervention.
  • Published in:Translational Neurodegeneration,
  • Study Type:Basic Research Study,
  • Source: PMC10683276, PMID: 38012808, DOI: 10.1186/s40035-023-00386-6
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