Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states

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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BibTeX RIS

BibTeX

@misc{barriga2026characterization,
  title = {{Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states}},
  author = {G. Garcia-Diaz Barriga and D. Rosebrock and H. Renner and I. Meyer and G. Penalosa-Ruiz and M. M. Firulyova and M. Simon and T. Yang and G. M. Serratto and F. Zoppetti and W. Müller and A. Illarionova and K. Heise and R. Kuhn and H. von der Kammer and B. Zimmer and D. Gruber-Schoffnegger},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.26.747247},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.26.747247v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states
AU  - G. Garcia-Diaz Barriga
AU  - D. Rosebrock
AU  - H. Renner
AU  - I. Meyer
AU  - G. Penalosa-Ruiz
AU  - M. M. Firulyova
AU  - M. Simon
AU  - T. Yang
AU  - G. M. Serratto
AU  - F. Zoppetti
AU  - W. Müller
AU  - A. Illarionova
AU  - K. Heise
AU  - R. Kuhn
AU  - H. von der Kammer
AU  - B. Zimmer
AU  - D. Gruber-Schoffnegger
PY  - 2026
DA  - 2026/08/26
PB  - bioRxiv
DO  - 10.64898/2026.08.26.747247
UR  - https://www.biorxiv.org/content/10.64898/2026.08.26.747247v1
AB  - 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.
ER  -

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