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    Area of Science:

    • Neuroscience
    • Genomics
    • Molecular Biology

    Background:

    • Long non-coding RNAs (lncRNAs) are key regulators in biological processes.
    • Dysregulation of lncRNAs is increasingly linked to aging and Alzheimer's disease (AD).

    Purpose of the Study:

    • To map the spatial expression of lncRNAs in the aged human dorsolateral prefrontal cortex.
    • To identify lncRNAs involved in Alzheimer's disease (AD) pathogenesis.

    Main Methods:

    • Spatial transcriptomics analysis of 78 postmortem brain sections from 21 individuals (ROSMAP cohort).
    • Network analysis to identify gene modules and differentially expressed (DE) lncRNAs in AD.
    • Gene set enrichment analysis and statistical modeling to explore functional roles.

    Main Results:

    • lncRNAs displayed greater subregion-specific expression than mRNAs in the aged brain.
    • 193 gene modules were identified, including lncRNA-enriched modules involved in critical biological processes.
    • AD DE lncRNAs showed higher subregion specificity than AD DE mRNAs and were linked to epigenetic regulation, including HDAC targets like OIP5-AS1.

    Conclusions:

    • This study provides a spatial lncRNA expression resource for the aged human brain.
    • lncRNA OIP5-AS1 interactions with HDAC proteins (e.g., HDAC11) are associated with AD hallmarks like tau tangles and plaque burden.
    • lncRNAs represent potential functional players and therapeutic targets in Alzheimer's disease pathogenesis.