Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism

ABSTRACT: Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and sequence variants are major risk factors for late onset Alzheimer’s disease (LOAD). Using a reporter model, we observed a gradual upregulation of TREM2 with increasing plaque proximity. Isolated microglia were sorted based on reporter expression, to determine fluorodeoxyglucose (FDG) uptake and the metabolomic, lipidomic, and transcriptomic signatures. Uptake of FDG correlated with the gradual increase of TREM2 expression. TREM2 expression improved cellular redox, energetics, and cholesterol homeostasis in the presence or absence of amyloid pathology. Bulk RNA sequencing analysis identified major changes in immunometabolic pathways. Genes associated with oxidative phosphorylation or cholesterol homeostasis were enriched in the TREM2 high expressing clusters. Finally, chronic treatment with a brain penetrant TREM2 agonist identified a window of TREM2 expression where microglia are most accessible for protective responses providing important information for the current efforts to bring TREM2 agonists into the clinic.

ORGANISM(S): Mus musculus

PROVIDER: GSE271074 | GEO | 2025/12/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism.

Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and sequence variants are major risk factors for late onset Alzheimer’s disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling, we generated a TREM2 reporter mouse model and observed a gradual upregulation of reporter expression with increasing plaque proximity. Isolated microglia were sorted based on reporter expression and their transcriptomic profiles acquired in both wildtype and APP transgenic animals, allowing us to disentangle TREM2 versus pathology-specific effects. Bulk RNA36 sequencing highlighted TREM2 level-dependent changes in major immunometabolic pathways, with enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. To confirm these findings, we next analysed uptake of fluorodeoxyglucose (FDG) and examined metabolomic and lipidomic profiles. Again, independent of Aβ pathology, TREM2 expression correlated with uptake of FDG as well as increased cellular redox, energetics, and cholesterol homeostasis. Finally, we performed chronic treatment with a brain penetrant TREM2 agonist and identified a window of TREM2 expression where microglia are most responsive. Thus, our data provide novel insights into TREM2-mediated regulation of microglial metabolic function and informs current efforts to bring TREM2 agonists into clinical application.

2025-12-01 | GSE295016 | GEO

Increased glucose uptake in hippocampus as a surrogate biomarker of metabolic reconfiguration of microglia in Alzheimer’s disease

Project description:Microglia is dynamically reprogrammed according to the progression of Alzheimer’s disease (AD). However, clinical translation into biomarker development for functional change in microglia has not been achieved. Here, we find the close association of the metabolic reconfiguration of microglia with increased hippocampal glucose uptake, which can be noninvasively estimated by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). We found that increased FDG activity in the hippocampus of an AD mouse model depended on microglial uptake. Single-cell RNA-sequencing of the hippocampus showed the changes of glucose metabolism profiles including glucose transporters, glycolysis and oxidative phosphorylation mainly occurred in microglia. A subset of microglia with high glucose transporters with defective glycolysis and oxidative phosphorylation was increased according to disease progression. Furthermore, we also found a positive association between a soluble TREM2 of cerebrospinal fluid, a marker of microglial activation, and hippocampal FDG uptake as a human study. We identified a reconfiguration of microglial glucose metabolism in the hippocampus of AD and suggested a feasible imaging biomarker based on widely used FDG PET to reflect microglial metabolic profiles.

2021-09-08 | GSE150934 | GEO

TREM2 regulates microglial cell activation in response to demyelination in vivo

Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),

2015-07-06 | E-GEOD-70475 | biostudies-arrayexpress

Expression data from WT and TREM2 deficient microglia in a mouse model of Alzheimer's disease

Project description:We examined the role of TREM2 on microglia responses to amyloid-beta deposition in a mouse model of Alzheimer's disease Microglia were FACS-purified from 8.5 month old WT, Trem2-/-, 5XFAD, and Trem2-/- 5XFAD mice

2015-03-13 | E-GEOD-65067 | biostudies-arrayexpress

Expression data from WT and TREM2 deficient microglia in response to cuprizone mediated demyelination

Project description:We examined the role of TREM2 on microglia responses to demyelination Microglia were FACS-purified from WT or Trem2-/- mice fed with 0.2% cuprizone diet.

2015-04-22 | E-GEOD-66926 | biostudies-arrayexpress

Gene expression study in Positron Emission Tomography (PET) positive abdominal aortic aneurysms

Project description:This study aims at identifying genes involved in this metabolic activation potentially related to rupture. A genome-wide transcriptomic analysis was performed on biopsies collected from patients with a Fluorodeoxyglucose (FDG) uptake both in the positive spot (A+Pos) and in a distant negative site of the same aneurysm (A+Neg). These paired biopsies were further compared to samples collected from (abdominal aortic aneurysms) AAA patients with no FDG uptake (A0) in order to discriminate biological alterations associated with FDG uptake, to detect new systemic biomarkers correlated with a higher risk of rupture and to identify new pathways involved in the progression and rupture of AAA).

2015-02-09 | E-MTAB-3175 | biostudies-arrayexpress

TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration

Project description:Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to neurodegenerative disease risk. However, the function of TREM in neurodegeneration is still unclear. Here we investigated the role of microglial TREM2 in TAR-DNA binding protein 43 kDa (TDP-43)-related neurodegeneration using viral-mediated and transgenic mouse models. We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia, and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry and surface plasmon resonance analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in ALS patient tissues. We computationally identified the region within hTDP-43 that interacts with TREM2. Our data highlights that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection effects of microglia in TDP-43-related neurodegeneration.

2022-08-12 | PXD029429 | Pride

iPSC-derived microglia carrying the TREM2 R47H/+ mutation are pro-inflammatory and promote synapse loss.

Project description:Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD). A number of mutations in the microglial protein TREM2 (triggering receptor expressed on myeloid cells 2) have been associated with increased risk for developing Alzheimer’s disease (AD), most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human iPSC-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a pro-inflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyper-responsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuron-microglia co-cultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.

2024-03-06 | GSE241858 | GEO

Glucose partitioning in the bone marrow micro-environment in acute myeloid leukaemia [bulk RNA-seq]

Project description:We used a positron emission tomography (PET) tracer 18F fluorodeoxyglucose ([18F]-FDG) and transcriptomic analysis to detect glucose uptake by cells in the bone marrow micro-environment with an MLL-AF9-induced mouse model. Leukaemic cells had the greatest glucose uptake. To determine whether glucose uptake is driven by intrinsic demand, we applied RNA-seq of sorted leukaemia cells (GFP+) and bone marrow micro-environment myeloid cells (GFP-CD11b+) from the MLL-AF9 transduced mouse model.

2023-04-14 | GSE227581 | GEO

Gene expression profiles of the standardized uptake value in 18F-fluorodeoxyglucose positron emission tomography in tripple negative breast cancer

Project description:The standardized uptake value (SUV), an indicator of the glucose uptake degree in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used as a prognostic factor in malignant tumors. We aimed to identify a signature reflecting prognostic SUV characteristics in triple negative breast cancer (TNBC). Transcriptome profiling was performed to identify a signature associated with the SUV in TNBC patients who underwent preoperative FDG-PET. We defined a signature significantly associated with the SUV (|r| > .35; P < .01). The SUV signature showed independent clinical utility for predicting BRC prognosis. Integrative analysis demonstrated a significance of the signature in predicting the response to immunotherapy and revealed that a signaling axis defined by TP53-FOXM1 and its downstream effectors in glycolysis-gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our results reveal characteristics of glucose uptake captured by FDG-PET, supporting an understanding of glucose metabolism as well as poor prognosis in TNBC patients with a high SUV.

2020-03-18 | GSE135565 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data