Products Cited in Publications Worldwide A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer's disease

A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer's disease

Verena Haage; John F. Tuddenham; Natacha Comandante-Lou; Alex Bautista; Anna Monzel; Rebecca Chiu; Masashi Fujita; Frankie G. Garcia; Prabesh Bhattarai; Ronak Patel; Alice Buonfiglioli; Juan Idiarte; Mathieu Herman; Alison Rinderspacher; Angeliki Mela; Wenting Zhao; Michael G. Argenziano; Julia L. Furnari; Matei A. Banu; Donald W. Landry; Jeffrey N. Bruce; Peter Canoll; Ya Zhang; Tal Nuriel; Caghan Kizil; Andrew A. Sproul; Lotje D. de Witte; Peter A. Sims; Vilas Menon; Martin Picard; Philip L. De Jager

DOI:

Abstract

While efforts to identify microglial subtypes have recently accelerated, the relation of transcriptomically defined states to function has been largely limited to in silico annotations. Here, we characterize a set of pharmacological compounds that have been proposed to polarize human microglia towards two distinct states – one enriched for AD and MS genes and another characterized by increased expression of antigen presentation genes. Using different model systems including HMC3 cells, iPSC-derived microglia and cerebral organoids, we characterize the effect of these compounds in mimicking human microglial subtypes in vitro. We show that the Topoisomerase I inhibitor Camptothecin induces a CD74high/MHChigh microglial subtype which is specialized in amyloid beta phagocytosis. Camptothecin suppressed amyloid toxicity and restored microglia back to their homeostatic state in a zebrafish amyloid model. Our work provides avenues to recapitulate human microglial subtypes in vitro, enabling functional characterization and providing a foundation for modulating human microglia in vivo.

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Copanlisib

A1995261032568-63-098%

Copanlisib

15.0/2mg

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