A Pharmacological Toolkit for Human Microglia Identifies Topoisomerase I Inhibitors as Immunomodulators for Alzheimer's Disease

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.

Note:
Funding Information: The work was supported by the Chan-Zuckerberg Initiative’s Neurodegeneration Challenge Network grant CS-02018-191971. Some of the work also emerged from support from NIH/NIA grants R01 AG070438, U01 AG061356, RF1 AG057473, R01AG048015. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM007367 and by the National Cancer Institute of the National Institutes of Health under Award Number F30CA261090.

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: All procedures described in the present study were approved by and complied with the guidelines of the Institutional Animal Care and Use Committee of the Nathan Kline Institute and Columbia University Medical Center (Animal Care Protocol AC-AABR4602 (Y1 M05).

Keywords: Human microglia, single cell, microglia subtypes, in silico drug screening, in vitro models for human microglial subtypes, mitochondrial phenotyping

Suggested Citation: Suggested Citation

Haage, Verena Claudia and Tuddenham, John F. and Comandante-Lou, Natacha and Bautista, Alex and Monzel, Anna and Chiu, Rebecca and Fujita, Masashi and Garcia, Frankie G. and Bhattarai, Prabesh and Patel, Ronak and Buonfiglioli, Alice and Idiarte, Juan and Herman, Mathieu and Rinderspacher, Alison and Mela, Angeliki and Zhao, Wenting and Argenziano, Michael and Furnari, Julia L. and Banu, Matei and Landry, Donald W. and Bruce, Jeffrey N. and Canoll, Peter and Zhang, Ya and Nuriel, Tal and Kizil, Caghan and Sproul, Andrew and de Witte, Lot D. and Sims, Peter A. and Menon, Vilas and Menon, Vilas and Picard, Martin and De Jager, Philip L. and Administrator, Sneak Peek, A Pharmacological Toolkit for Human Microglia Identifies Topoisomerase I Inhibitors as Immunomodulators for Alzheimer's Disease. Available at SSRN: https://ssrn.com/abstract=4895285 or http://dx.doi.org/10.2139/ssrn.4895285

This version of the paper has not been formally peer reviewed.