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Predicting Relevant Microglia-Associated Cell-Cell Communication Pathways in Alzheimer's Disease: A Role for SPP1
Janssen M Kotah1, Marina Trombetta Lima1, Esmée C Dragt1
1Department of Biomedical Sciences, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Abstract:
Microglia play a key role in the pathophysiology of Alzheimer's Disease (AD) and their increased heterogeneity likely affects disease progression. We previously identified distinct microglial signatures that were enriched in AD donors and associated with amyloid and tau, respectively. Here we generated a snRNAseq dataset from postmortem control and AD cases and analyzed alterations in cell-cell communication pathways that might be relevant to AD pathophysiology. One signaling pathway perturbed in AD cases involved SPP1, and while this pathway was also present in control samples, microglia-microglia SPP1 signaling was restricted to AD donors. Further analyses within microglia-microglia signaling predict AD-specific induction of GAS6-AXL signaling (from inflammatory and ribosomal microglia), and SPP1-ITGAV/ITGB5 signaling (from disease-associated and inflammatory microglia, among others). Together, these findings might in part explain the increased microglia phagocytic profile described in AD. RNAscope confirmed enrichment of SPP1 expressing microglia near amyloid plaques in AD brain tissue samples. These data indicate altered cellular communications between microglia in the AD brain.
Insights
Microglia communication changes in Alzheimer's Disease (AD). Specific signaling pathways like SPP1 are altered, impacting microglial function and potentially disease progression in the AD brain.
Area of Science:
- Neuroscience
- Immunology
- Genomics
Background:
- Microglia, the brain's immune cells, are crucial in Alzheimer's Disease (AD) pathophysiology.
- Increased microglial heterogeneity is observed in AD and may influence disease progression.
- Distinct microglial signatures associated with amyloid and tau pathologies have been previously identified.
Purpose of the Study:
- To analyze alterations in cell-cell communication pathways in microglia from postmortem control and AD cases.
- To investigate the role of specific signaling pathways, such as SPP1, in AD pathophysiology.
- To understand how altered microglia communication contributes to AD-related changes.
Main Methods:
- Generation and analysis of single-nucleus RNA sequencing (snRNAseq) data from postmortem human brain samples (control and AD).
- Computational analysis of cell-cell communication pathways.
- RNAscope in situ hybridization to validate findings in brain tissue.
Main Results:
- A perturbed signaling pathway involving Secreted Phosphoprotein 1 (SPP1) was identified in AD cases.
- Microglia-to-microglia SPP1 signaling was specifically restricted to AD donors, unlike in controls.
- AD-specific induction of GAS6-AXL and SPP1-ITGAV/ITGB5 signaling pathways within microglia was predicted.
- SPP1-expressing microglia were found enriched near amyloid plaques in AD brain tissue.
Conclusions:
- Altered cellular communications between microglia are evident in the AD brain.
- Specific signaling pathways, including SPP1 and GAS6-AXL, are dysregulated in AD microglia.
- These communication changes may contribute to the observed increase in microglial phagocytic activity in AD.
