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Microglial PLXDC2 Modulates Aβ Phagocytosis and Inflammatory Responses
Yoonah R Oh1,2, Se Eun Park1,2, Hee Kyung Kim1,2
1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
Abstract:
Microglia have emerged as key regulators in Alzheimer's disease (AD), yet the molecular factors driving their dysfunction remain unclear. Through integrative transcriptomic and proteomic analyses, we identified PLXDC2, a transmembrane receptor, as a protein consistently upregulated in the AD brain and cerebrospinal fluid. Single-nucleus RNA-seq confirmed its microglia-specific enrichment, particularly in lipid-processing, phagocytic, and inflammatory subclusters. Functional assays revealed that PLXDC2 overexpression in BV2 microglial cells impaired Aβ uptake and suppressed pro-inflammatory cytokines Il-6 and Il-1β, without altering lipid droplet formation. These findings indicate that PLXDC2 plays a regulatory role in critical microglial functions and may drive AD pathogenesis by disrupting phagocytic activity and immune responses.
Insights
The transmembrane receptor PLXDC2 is upregulated in Alzheimer's disease (AD) brains, impairing microglial phagocytosis and immune responses. This suggests PLXDC2 dysfunction contributes to AD pathogenesis by affecting key microglial functions.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia are crucial in Alzheimer's disease (AD) pathogenesis.
- Molecular drivers of microglial dysfunction in AD are not fully understood.
Purpose of the Study:
- Identify molecular factors contributing to microglial dysfunction in AD.
- Investigate the role of the transmembrane receptor PLXDC2 in AD.
Main Methods:
- Integrative transcriptomic and proteomic analyses of AD brain and cerebrospinal fluid.
- Single-nucleus RNA sequencing (snRNA-seq) for cell-type specific gene expression.
- Functional assays using BV2 microglial cells to assess PLXDC2 effects on phagocytosis and cytokine production.
Main Results:
- PLXDC2 was consistently upregulated in the AD brain and cerebrospinal fluid.
- snRNA-seq revealed PLXDC2 is enriched in microglia, particularly in lipid-processing, phagocytic, and inflammatory subclusters.
- Overexpression of PLXDC2 in microglial cells impaired amyloid-beta (Aβ) uptake and suppressed pro-inflammatory cytokines (Il-6, Il-1β).
Conclusions:
- PLXDC2 plays a regulatory role in microglial phagocytic and inflammatory functions.
- PLXDC2 dysregulation may contribute to Alzheimer's disease pathogenesis by disrupting microglial activity and immune responses.
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