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Single-cell peripheral immunoprofiling of Alzheimer's and Parkinson's diseases
Thanaphong Phongpreecha1,2,3, Rosemary Fernandez3, Dunja Mrdjen3
1Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, USA.
Insights
Investigating peripheral blood mononuclear cells (PBMCs) in Alzheimer's disease (AD) revealed distinct signaling pathway alterations. Reduced PLCγ2 activation in PBMCs suggests it as a potential therapeutic target for AD.
Area of Science:
- Immunology
- Neuroscience
- Genetics
Background:
- Peripheral blood mononuclear cells (PBMCs) offer potential insights into the pathogenesis of neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD).
- Understanding immune cell function in AD is crucial for identifying novel therapeutic targets and biomarkers.
Purpose of the Study:
- To investigate intracellular signaling pathways within PBMC subsets in individuals with AD compared to controls.
- To identify specific immune cell signaling alterations associated with AD pathogenesis.
- To explore the potential of PLCγ2 as a therapeutic target for AD.
Main Methods:
- Analysis of PBMC samples from 132 well-characterized participants.
- Utilized seven canonical immune stimulants and mass cytometry to identify 35 PBMC subsets.
- Quantified 15 intracellular signaling markers at the single-cell level.
- Developed machine learning models to enhance predictive power.
Main Results:
- Identified three key intracellular signaling pathways in PBMCs from AD patients versus controls.
- Observed reduced activation of phospholipase C gamma 2 (PLCγ2) across multiple cell types and stimulations in AD.
- Found selectively variable activation of STAT1 and STAT5, dependent on the stimulant and cell type.
Conclusions:
- The findings support the association between reduced PLCγ2 activity and decreased AD risk, linked to a rare coding variant in the PLCG2 gene.
- Enhanced PLCγ2 activity is proposed as a potential therapeutic strategy for AD.
- PBMC signaling pathways, particularly PLCγ2 activation, may serve as pharmacodynamic biomarkers for AD therapies.
Abstract:
Peripheral blood mononuclear cells (PBMCs) may provide insight into the pathogenesis of Alzheimer's disease (AD) or Parkinson's disease (PD). We investigated PBMC samples from 132 well-characterized research participants using seven canonical immune stimulants, mass cytometric identification of 35 PBMC subsets, and single-cell quantification of 15 intracellular signaling markers, followed by machine learning model development to increase predictive power. From these, three main intracellular signaling pathways were identified specifically in PBMC subsets from people with AD versus controls: reduced activation of PLCγ2 across many cell types and stimulations and selectively variable activation of STAT1 and STAT5, depending on stimulant and cell type. Our findings functionally buttress the now multiply-validated observation that a rare coding variant in PLCG2 is associated with a decreased risk of AD. Together, these data suggest enhanced PLCγ2 activity as a potential new therapeutic target for AD with a readily accessible pharmacodynamic biomarker.
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