Predicting Relevant Microglia-Associated Cell-Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1

Area of Science:

• Neuroscience
• Immunology
• Genomics

Background:

• Microglia, the brain's immune cells, are crucial in Alzheimer's Disease (AD) pathogenesis.
• Microglial heterogeneity is increasingly recognized as a factor influencing AD progression.
• Previous work identified AD-enriched microglial signatures linked to amyloid and tau pathologies.

Purpose of the Study:

• To investigate alterations in cell-cell communication pathways involving microglia in the Alzheimer's Disease brain.
• To identify specific signaling pathways perturbed in AD cases using single-nucleus RNA sequencing (snRNAseq).
• To explore the functional implications of altered microglia communication in AD pathophysiology.

Main Methods:

• Generation and analysis of snRNAseq data from postmortem control and AD brain samples.
• Computational analysis of cell-cell communication pathways, focusing on microglia.
• Validation of specific microglial signaling pathway enrichment using RNAscope in AD brain tissue.

Main Results:

• A signaling pathway involving SPP1 was perturbed in AD cases.
• Microglia-to-microglia SPP1 signaling was uniquely identified in AD donors, not in controls.
• AD-specific induction of GAS6-AXL and SPP1-ITGAV/ITGB5 signaling pathways between microglia subtypes was predicted.
• SPP1-expressing microglia were found enriched near amyloid plaques in AD brain tissue.

Conclusions:

• Altered cell-cell communication networks exist between microglia in the Alzheimer's Disease brain.
• Specific signaling pathways, such as SPP1 and GAS6-AXL, are dysregulated in AD microglia.
• These communication changes may contribute to the enhanced microglial phagocytic activity observed in AD.