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  3. 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

  • bioRxiv. 2024 Feb 6:2024.02.06.579103. doi: 10.1101/2024.02.06.579103.
Verena Haage # 1,  John F Tuddenham # 1 2,  Natacha Comandante-Lou # 1,  Alex Bautista 1,  Anna Monzel 3,  Rebecca Chiu 1,  Masashi Fujita 1,  Frankie G Garcia 1,  Prabesh Bhattarai 4,  Ronak Patel 5,  Alice Buonfiglioli 6,  Juan Idiarte 4,  Mathieu Herman 4,  Alison Rinderspacher 7,  Angeliki Mela 8,  Wenting Zhao 2,  Michael G Argenziano 9,  Julia L Furnari 9,  Matei A Banu 9,  Donald W Landry 7,  Jeffrey N Bruce 9,  Peter Canoll 8,  Ya Zhang 1,  Tal Nuriel 4,  Caghan Kizil 4,  Andrew A Sproul 5,  Lotje D de Witte 6,  Peter A Sims 2,  Vilas Menon 1,  Martin Picard 3 10 11 12,  Philip L De Jager 1
Affiliations

Affiliations

  • 1 Center for Translational & Computational Neuroimmunology, Neuroimmunology Division, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, United States.
  • 2 Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, United States.
  • 3 Department of Psychiatry, Division of Behavioral Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, USA.
  • 4 Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, United States.
  • 5 Department of Pathology and Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY 10032, United States.
  • 6 Department of Psychiatry, Icahn School of Medicine, 1460 Madison Avenue, New York, NY, 10029, United States.
  • 7 Department of Medicine, Columbia University, New York, NY 10032, United States.
  • 8 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • 9 Department of Neurological Surgery, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 10 Department of Neurology, H. Houston Merritt Center, Columbia Translational Neuroscience Initiative, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, USA.
  • 11 New York State Psychiatric Institute, New York, USA.
  • 12 Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health, New York, NY, USA.
  • # Contributed equally.
PMID: 38370689 DOI: 10.1101/2024.02.06.579103
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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