Dataset Information

A cross-disease human microglial framework identifies disease-enriched subsets and tool compounds for microglial polarization.

ABSTRACT: a. Human microglia play a pivotal role in neurological diseases, but few targeted therapies that directly modulate microglial state or function exist due to an incomplete understanding of microglial heterogeneity. We use single-cell RNA sequencing to profile live human microglia from autopsies or surgical resections across diverse neurological diseases and central nervous system regions. We observe a central divide between oxidative and heterocyclic metabolism and identify subsets associated with antigen presentation, motility, and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope-immunofluorescence pipeline and leverage our dataset as a classification resource, finding that iPSC model systems recapitulate substantial in vivo heterogeneity. Finally, we identify and validate candidates for chemically inducing subtype-specific states in vitro, showing that Camptothecin downregulates the transcriptional signature of disease-enriched subsets and upregulates a signature previously shown to be depleted in Alzheimer’s.

INSTRUMENT(S): Bruker Daltonics timsTOF series

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Microglial Cell

SUBMITTER: John Tuddenham

LAB HEAD: Philip L. De Jager

PROVIDER: PXD033844 | Pride | 2025-05-19

REPOSITORIES: Pride

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A cross-disease resource of living human microglia identifies disease-enriched subsets and tool compounds recapitulating microglial states.

Tuddenham John F JF Taga Mariko M Haage Verena V Marshe Victoria S VS Roostaei Tina T White Charles C Lee Annie J AJ Fujita Masashi M Khairallah Anthony A Zhang Ya Y Green Gilad G Hyman Bradley B Frosch Matthew M Hopp Sarah S Beach Thomas G TG Serrano Geidy E GE Corboy John J Habib Naomi N Klein Hans-Ulrich HU Soni Rajesh Kumar RK Teich Andrew F AF Hickman Richard A RA Alcalay Roy N RN Shneider Neil N Schneider Julie J Sims Peter A PA Bennett David A DA Olah Marta M Menon Vilas V De Jager Philip L PL

Nature neuroscience 20241015 12

Human microglia play a pivotal role in neurological diseases, but we still have an incomplete understanding of microglial heterogeneity, which limits the development of targeted therapies directly modulating their state or function. Here, we use single-cell RNA sequencing to profile 215,680 live human microglia from 74 donors across diverse neurological diseases and CNS regions. We observe a central divide between oxidative and heterocyclic metabolism and identify microglial subsets associated w ...[more]

PMID: 39406950

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	DMSO1_analysis.tdf_bin	Other
	DMSO2_analysis.tdf	Other
	DMSO2_analysis.tdf_bin	Other
	DMSO3_analysis.tdf	Other