Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genomics
• Epigenetics

Background:

• Circular RNAs (circRNAs) regulate gene expression and RNA-protein interactions.
• Epitranscriptomic modifications of circRNAs are implicated in neurodegeneration.
• The role of circRNAs in Alzheimer's disease (AD) pathogenesis is not well understood.

Purpose of the Study:

• To explore circRNA-mediated regulatory mechanisms in Alzheimer's disease (AD) using single-nucleus RNA sequencing (snRNA-seq) and spatial epigenomics.
• To identify circRNA-driven molecular changes and their effects on neuronal and glial function in AD.
• To advance the understanding of AD pathogenesis through the lens of circRNA epitranscriptomics.

Main Methods:

• Utilized snRNA-seq data from the Allen Institute and AMP-AD Knowledge Portal.
• Integrated spatial epigenomics data for histone modifications and chromatin accessibility.
• Developed and applied a deep neural network (DNN) model, CircEpiNet, to predict phenotypic impacts of circRNA modifications.

Main Results:

• Identified 14 circRNAs with significant epitranscriptomic modifications in AD.
• Demonstrated circAPP hyper-methylation disrupting amyloid precursor protein processing.
• Showed circTREM2 hyper-methylation correlating with microglial activation and circPGC1A hypo-methylation affecting mitochondrial biogenesis.

Conclusions:

• Identified essential roles of circRNAs in Alzheimer's disease progression.
• Established a robust multi-omic deep learning framework for studying circRNA epitranscriptomics in AD.
• Provided insights into potential therapeutic targets for Alzheimer's disease.