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Basic Science and Pathogenesis.

Jiahui Liu1,2, Jie Zhang1, Kun Huang1

  • 1Indiana University, School of Medicine, Indianapolis, IN, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
PubMed
Summary
This summary is machine-generated.

This study reveals key cell-cell interactions in Alzheimer's disease (AD) using a novel computational pipeline. Findings highlight interactions in vascular dysfunction, synaptic deficits, and inflammation, guiding future therapeutic development for AD.

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Area of Science:

  • Neuroscience
  • Genomics
  • Computational Biology

Background:

  • Alzheimer's disease (AD) involves complex neurovascular, inflammatory, and synaptic changes.
  • Current understanding of intercellular communication networks in AD is limited.
  • Existing single-cell and bulk RNA sequencing studies offer cell-type-specific insights but lack network-level communication data.

Purpose of the Study:

  • To introduce a novel computational pipeline for identifying and prioritizing robust cell-cell interactions in Alzheimer's disease.
  • To systematically analyze intercellular communication networks driving AD pathology.
  • To provide a foundation for experimental validation and therapeutic development in AD.

Main Methods:

  • Developed an integrative computational pipeline combining cell prioritization (DEGAS) with intercellular communication inference (CellChat).
  • Integrated large-scale RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) data from multiple datasets (>2.4 million cells).
  • Validated ligand-receptor co-expression via correlation analysis and identified linked pathways using differential gene expression (DEG) and gene ontology (GO) analyses.

Main Results:

  • Consistently identified key cell-cell interactions across datasets, including FN1-SDC4 (endothelial cells-astrocytes) linked to blood-brain barrier dysfunction.
  • Discovered CADM1-CADM1 interactions (oligodendrocytes-OPCs) associated with synaptic organization deficits and BSG-PPIA (endothelial cells) linked to vascular inflammation.
  • Identified JAM3-JAM3 and PTPRM-PTPRM interactions in control contexts, suggesting roles in synaptic maintenance and axonal guidance.

Conclusions:

  • The novel pipeline effectively integrates multi-omics data to reveal robust intercellular communication networks in Alzheimer's disease.
  • Identified specific cell-cell interactions provide critical insights into AD pathology mechanisms.
  • Findings pave the way for targeted experimental validation and the development of novel AD therapeutics.