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Protective variant in PLCγ2 mitigates Alzheimer’s disease associated pathology via enhancing beneficial microglia functions

GSE277167 Mus musculus (mouse) RNA-seq (gene expression) 31 samples Submitted 2024/09/16 Platform GPL24247
At a glance

RNA-seq (gene expression) · mouse · 31 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
31 samples: 7 conditions, mostly with about 4 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.
Summary (written by the submitters)
PLCγ2-P522R (phospholipase C gamma 2, proline 522 to arginine) is a protective variant that reduces the risk for late onset Alzheimer’s disease (LOAD). Recently, it was shown to decrease β-amyloid pathology in 5XFAD mouse model of AD. In this study, our goal was to investigate the protective functions of PLCγ2-P522R variant in less aggressive mouse model of AD as well as to assess underlying mechanisms at the molecular and cellular level using mouse and human microglia models.
Read the full summary ↓
The effects of the protective PLCγ2-P522R variant on microglia activation, AD-related β-amyloid and neuronal pathologies, as well as behavioral changes were investigated in PLCγ2-P522R knock-in mice crossbred with an APP/PS1 mouse model of AD. Transcriptomic, proteomic, and functional studies were carried out in cultured and acutely isolated adult PLCγ2-P522R mouse microglia to study molecular mechanisms. Finally, microglia-like cell models generated from blood and skin biopsy samples of the PLCγ2-P522R variant carriers were employed to translate the key findings in human cells. Our results demonstrate that the PLCγ2-P522R variant reduces brain β-amyloid plaque burden of APP/PS1 mice. Simultaneously, PLCγ2-P522R variant increased non-proinflammatory microglia activation and microglia clustering around β-amyloid plaques, leading to reduced β-amyloid plaque-associated neuronal dystrophy. In cultured mouse primary microglia, PLCγ2-P522R variant decreased accumulation of large lipid droplets, reduced cell stress, and increased acute response to strong inflammatory stimuli. Transcriptomic and proteomic analyses in acutely isolated adult mouse microglia as well as in human monocyte-derived microglial cells showed that PLCγ2-P522R upregulates mitochondrial fatty acid oxidation and downregulates inflammatory/interferon signaling pathways. Accordingly, PLCγ2-P522R increased mitochondrial respiration in iPSC -derived microglial cells. Together, these findings suggest that PLCγ2-P522R variant exerts protection against AD-associated β-amyloid and neuronal pathologies via enhancing microglial barrier formation around β-amyloid plaques, but suppressing pro-inflammatory activation. Observed changes in fatty acid metabolism and mitochondrial flexibility as well as the downregulation of genes involved in inflammatory signaling pathways suggest that these protective effects of the PLCγ2-P522R variant are mediated through an anti-ageing mechanism.
This dataset
Open GSE277167 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 GSE277167_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 PRJNA1160893 and SRA study SRP532629. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗
Study design
7 conditions, mostly with about 4 replicates each
microglia, A-/wt/wt, female, mouse ×7 microglia, A+/ki/ki, female, mouse ×4 microglia, A+/wt/wt, female, mouse ×4 microglia, A-/ki/ki, male, mouse ×4 temporo-occipital cortex, A+/Pki/ki, female, … ×4 temporo-occipital cortex, A+/Pwt/wt, female, … ×4 microglia, A-/wt/wt, male, mouse ×3 temporo-occipital cortex, A-/Pwt/wt, female, … ×1

Supports a between-group comparison across 30 samples.

How we read this: 7 replicated groups read from 31 sample titles; they account for 30 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
Datasets on a similar topic

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