Integrated Spatial and Single-Nuclei Transcriptomic Analysis of Long Non-Coding RNAs in Alzheimer’s Disease

  1. Bernard Ng
  2. Denis R. Avey
  3. Faraz Sultan
  4. Katia de Paiva Lopes
  5. Masashi Fujita
  6. Devin Saunders
  7. Ricardo A. Vialle
  8. Himanshu Vyas
  9. Nicola A. Kearns
  10. Shinya Tasaki
  11. Artemis Iatrou
  12. Sashini De Tissera
  13. Amiko Krisa Lagrimas
  14. Tien-Hao Chang
  15. Jishu Xu
  16. Chunjiang Yu
  17. Vilas Menon
  18. Chris Gaiteri
  19. Philip L. De Jager
  20. David A. Bennett
  21. Yanling Wang
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Abstract

Background

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). To investigate the spatial and cellular distribution of lncRNAs in the aging brain, we leveraged published spatial transcriptomics (ST), single-nucleus RNA sequencing (snRNA-seq), and bulk RNA-seq datasets from the dorsolateral prefrontal cortex (DLPFC) of ROSMAP participants with and without pathological AD.

Results

LncRNAs exhibited greater subregion-specific expression than mRNAs, with enrichment in antisense and lincRNA biotypes. Subregion-enriched lncRNAs were generally not cell-type specific, and vice versa. Differential expression analysis of ST data identified AD-associated lncRNAs with distinct spatial patterns and moderate overlap with differentially expressed (DE) lncRNAs from bulk RNA-seq. Gene set enrichment revealed their involvement in chromatin remodeling, epigenetic regulation, and RNA metabolism. We also identified AD DE lncRNAs across major brain cell types using snRNA-seq but overlap with ST DE lncRNAs was limited. Among previously reported lncRNAs, OIP5-AS1 was consistently upregulated in AD in all cortical subregions. Antisense oligonucleotide (ASO) knockdown of OIP5-AS1 in iPSC-derived microglia led to upregulation of pro-inflammatory genes and downregulation of DNA replication and repair pathways. Immunoassays confirmed increased secretion of pro-inflammatory cytokines. The knockdown expression pattern was enriched for microglia-specific AD DE genes and microglia states.

Conclusions

This study provides a spatial and cellular map of lncRNAs in the aging human cortex and identifies subregion-and cell-type-enriched DE lncRNAs in AD. Our findings implicate OIP5-AS1 in microglial activation, suggesting its potential contribution to AD pathogenesis.

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