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Researchers analyzed over 236,000 microglial cell nuclei from 84 human donors to identify genes controlling microglial behavior in Alzheimer's disease. Using computational methods including gene regulatory network inference and trajectory analysis, they identified IKZF1 as a key transcription factor regulating microglial state transitions in late-stage Alzheimer's, with activity particularly elevated in disease-associated microglia. The team also screened nearly 2,000 approved drugs and identified tafamidis and diflunisal as potential candidates for repurposing, though these require experimental validation.
Why it matters
This work identifies IKZF1 as a potential therapeutic target for modulating neuroinflammation in Alzheimer's disease, a disease compartment currently lacking approved treatments. The computational approach and drug screening results provide a foundation for developing microglial-targeted therapies, though the low confidence in current drug candidates indicates significant additional research is needed before clinical application.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background: Microglia drive neuroinflammation in Alzheimer’s disease (AD), yet no approved therapy targets this compartment. Human genome-wide association studies consistently implicate innate immune loci in AD risk, establishing microglial transcriptional programs as therapeutically relevant but pharmacologically underexploited targets. Objective: We sought to identify transcription factors (TFs) governing microglial state transitions computationally and to nominate structurally tractable drug repurposing candidates. Methods: We applied trajectory inference (PAGA), pseudobulk DESeq2, pySCENIC gene regulatory network (GRN) inference, CellChat, and virtual screening of 1,962 approved compounds to 236,002 microglial nuclei from 84 donors (SEA-AD atlas). Results: IKZF1 was the sole target TF retained under cisTarget v10 motif constraints, with peak regulon activity in LateAD-DAM (pseudotime {rho} = +0.309) and replication in an independent bulk cohort (GSE95587; adjusted P value = .004). CellChat identified SLIT2[->]ROBO2 from multiple neuron subtypes (predominantly inhibitory interneurons) as the top predicted pathway to microglia. Tafamidis ([->]IRF8) and diflunisal ([->]PPARG) were top virtual screening hits; all evaluated compounds failed the pre-specified selectivity threshold. Conclusions: IKZF1 is prioritised as a candidate late-disease microglial TF, supported by six convergent evidence dimensions including independent bulk replication. Tafamidis and diflunisal are low-confidence repurposing hypotheses requiring experimental validation.
Source: Single-cell gene networks nominate IKZF1 as an Alzheimer's microglial regulator