Abstract
Long non-coding RNAs (lncRNAs) are critical regulators of physiological and pathological processes, with their dysregulation increasingly implicated in aging and Alzheimer's disease (AD). Using spatial transcriptomics, we analyzed 78 postmortem brain sections from 21 ROSMAP participants to map the spatial expression of lncRNAs in the dorsolateral prefrontal cortex of aged human brains. Compared to mRNAs, lncRNAs exhibited greater subregion-specific expression, with enrichment in antisense and lincRNA biotypes. Network analysis identified 193 gene modules across eight subregions, including lncRNA-enriched modules involved in critical biological processes. We also identified AD differentially expressed (DE) lncRNAs, which showed greater subregion specificity than AD DE mRNAs. Gene set enrichment analysis highlighted the involvement of these AD DE lncRNAs in epigenetic regulation and chromatin remodeling, including enrichment for HDAC target genes such as OIP5-AS1. Statistical modeling suggested that interactions between OIP5-AS1 and HDAC proteins, particularly HDAC11, were associated with tau tangles in excitatory neurons and plaque burden in microglia. This study provides a comprehensive resource of lncRNA spatial expression in the aged human brain and uncovers potential functional roles of lncRNAs in AD pathogenesis.
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