Microglial PLXDC2 Modulates Aβ Phagocytosis and Inflammatory Responses

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.