Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states
Garcia-Diaz Barriga, G.; Rosebrock, D.; Renner, H.; Meyer, I.; Penalosa-Ruiz, G.; Firulyova, M. M.; Simon, M.; Yang, T.; Serratto, G. M.; Zoppetti, F.; Müller, W.; Illarionova, A.; Heise, K.; Kuhn, R.; von der Kammer, H.; Zimmer, B.; Gruber-Schoffnegger, D.
Show abstract
Microglia are central mediators of Alzheimers disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk, neuropathology and cognitive decline. To model this state experimentally, we screened AD-relevant perturbations in human induced pluripotent stem cell (hiPSC)-derived microglia and found that ferric ammonium citrate (FAC) reproducibly induced a DLaM-like state characterized by lipid accumulation, lysosomal dysfunction and impaired A{beta} phagocytosis. Using a transcriptomics-based state-reversion screen, we identified LY2090314 as a potent modulator that restored microglial function and induced a distinct lysosomal-metabolic state. These findings establish a framework for transcriptomic disease-state-guided therapeutic discovery in AD.
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