A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer's disease
Haage, V. C.; Tuddenham, J. F.; Comandante-Lou, N.; Bautista, A.; Monzel, A.; Chiu, R.; Fujita, M.; Garcia, F. G.; Bhattarai, P.; Patel, R.; Buonfiglioli, A.; Idiarte, J.; Herman, M.; Rinderspacher, A.; Mela, A.; Zhao, W.; Argenziano, M. G.; Furnari, J. L.; Banu, M. A.; Landry, D. W.; Bruce, J. N.; Canoll, P.; Zhang, Y.; Nuriel, T.; Kizil, C.; Sproul, A. A.; de Witte, L. D.; Sims, P. A.; Menon, V.; Picard, M.; De Jager, P. L.
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AbstractWhile 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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