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Microglia lineage relaxation towards a lymphoid-like state protects against Alzheimer’s disease.

GSE274896 Mus musculus (mouse) RNA-seq (gene expression) 33 samples Submitted 2025/08/07 Platform GPL19057
At a glance

RNA-seq (gene expression) · mouse · 33 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Mus musculus (mouse)
Samples
33 samples: 7 conditions, mostly with about 6 replicates eachGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
Lymphoid gene expression supports neuroprotective microglia functionNature · 2025
Summary (written by the submitters)
Amyloid plaques, a hallmark of Alzheimer's disease (AD), combine chemical and physical properties foreign to normal brain tissue. These "non-self" plaque patterns trigger local tissue responses in the brain, including microglia activation. Microglial response to the plaques can be both protective, aiming at amyloid clearance and neuroprotection, and harmful, associated with microglia-driven inflammation and neurotoxicity.
Read the full summary ↓
Here, we provide evidence that the microglial neuroprotective response to amyloid plaques involves a relaxation of the microglia lineage specification toward a lymphoid-like state. We found that a subpopulation of plaque-associated microglia downregulates the microglia lineage-specifying transcription factor PU.1 and de-represses several lymphoid-expressed genes, including those that play a key role in receptor-mediated signaling in B and T lymphocytes. The shift toward the lymphoid lineage is associated with an increased signaling capacity of PU.1low microglia that supports microglia maintenance at the plaque. Functionally, we show that PU.1low microglia protect neurons and reduce plaque-associated damage in a mouse model of amyloid deposition. Engineered genetic downregulation of PU.1 in microglia in the healthy brain emulates phenotypic features of plaque-associated microglia, promotes microglia-plaque association in disease, and protects against the loss of functional neuronal connections and associated behaviors, including cognition and memory in mice. We propose that the plaque-induced microglia lineage relaxation represents a novel mechanism of the microglial responses in the presence of AD pathology that is adaptive in nature and protective by function.
Published in
Lymphoid gene expression supports neuroprotective microglia function
Ayata P, Crowley JM, Challman MF et al. · Nature 2025 · PMID 41193812 · doi:10.1038/s41586-025-09662-z
This dataset
Open GSE274896 in finder → Find more mouse RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE274896_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1148425 and SRA study SRP526589. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 41193812) ↗
Study design
7 conditions, mostly with about 6 replicates each
Control Cortex microglia ×6 5xFAD Cortex microglia ×6 PU.1-low Cortex microglia ×6 PU.1-high Cortex microglia ×4 5xFAD+CSF1Ri Cortex microglia ×4 5xFAD;PU.1-low Cortex microglia ×4 5xFAD;PU.1-high Cortex microglia ×3

Supports a between-group comparison across 33 samples.

How we read this: 7 replicated groups read from 33 sample titles; they account for 33 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
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