We are excited to share a collaborative study, published in Cell Reports: “Topoisomerase I inhibition yields a CD74high/MHChigh human microglial subtype with enhanced Aβ uptake” (Haage et al., 2026).
Congratulations to all authors, and especially to first author Verena Haage and senior author Philip De Jager for leading this effort. Thanks as well to our lab members Prabesh Bhattarai. Our lab contributed the in vivo validation using our adult zebrafish Aβ42 model. Amyloid injection increased activated, amoeboid microglia and reduced synaptic density. Camptothecin reduced the activated microglia at both doses tested, and the higher dose preserved synapses.
Recent single-cell studies have described many distinct states of human microglia. A central open question is how these states relate to what the cells actually do. Building on a cross-disease atlas of living human microglia, the team used a drug-based strategy to reproduce one of these states in the lab and study it.
The study shows that the topoisomerase I inhibitors Camptothecin and Topotecan (an FDA-approved drug) drive human microglia toward a CD74high/MHChigh state. This state is marked by high expression of antigen-presentation genes. The effect held across HMC3 microglia-like cells, iPSC-derived microglia and cerebral organoids containing microglia. The same treatment suppressed a disease-enriched microglial signature linked to Alzheimer’s disease risk genes.
Functionally, these microglia:
- took up more amyloid-β while taking up less dextran and E. coli
- released less IL-6, IL-8 and MCP-1 in response to TNF-α
- entered a lower-energy metabolic state with a distinct mitochondrial profile
The work suggests a route to steer human microglia toward specific functional states, which could inform future Alzheimer’s therapies. As the authors note, much more work is needed before these compounds could be considered clinically.
Read the paper:
Haage V, Tuddenham JF, Comandante-Lou N, Bautista AR, Monzel AS, Garcia FG, Chiu R, Fujita M, Bhattarai P, White CC, Patel R, Buonfiglioli A, Idiarte J, Herman M, Rinderspacher A, Mela A, Zhao W, Argenziano MG, Furnari JL, Banu MA, Landry DW, Bruce JN, Canoll P, Zhang Y, Nuriel T, Sproul AA, de Witte LD, Sims PA, Menon V, Kizil C, Picard M, De Jager PL. Topoisomerase I inhibition yields a CD74high/MHChigh human microglial subtype with enhanced Aβ uptake. Cell Reports 45, 118031 (2026)
