Identifying brain-penetrant small-molecule modulators of human microglia using a cellular model of synaptic pruning.

ABSTRACT: Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation a promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in a scalable assay, we screened 489 CNS-penetrant compounds for modulation of microglial phagocytosis of human synaptosomes in a validated assay for microglia-mediated synaptic pruning. Compounds from the library that reduced phagocytosis by ≥2 standard deviations across the library without cytotoxicity were validated in secondary screens, with 28 of them further confirmed to reduce phagocytosis by 50% or more. These compounds comprise a wide range of therapeutic classes with different mechanisms of action, including immunosuppressants, kinase inhibitors, antipsychotics,

SUBMITTER: McCrea LT 

PROVIDER: S-EPMC12339681 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature