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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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

ORGANISM(S): Mus musculus

SUBMITTER: Marco Colonna

PROVIDER: E-GEOD-65067 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model.

Wang Yaming Y Cella Marina M Mallinson Kaitlin K Ulrich Jason D JD Young Katherine L KL Robinette Michelle L ML Gilfillan Susan S Krishnan Gokul M GM Sudhakar Shwetha S Zinselmeyer Bernd H BH Holtzman David M DM Cirrito John R JR Colonna Marco M

Cell 20150226 6

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment ...[more]

PMID: 25728668

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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

TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease

Project description:CD33-/- and/or TREM2-/- mice were crossed with the 5xFAD mouse model of Alzheimer’s disease to generate single and double CD33/TREM2 knock-out mice on 5xFAD background. Transcriptome and gene expression analyses were performed to analyze the impact of CD33 and/or TREM2 knock-out on the transcriptome of microglia in the context of amyloid pathology. The results revealed that CD33 and/or TREM2 knock-out reprogrammed microglial gene expression signatures in 5xFAD mice in an age-dependent manner. Differential gene expression in 5xFAD;CD33-/- microglia depended on the presence of TREM2. These data suggest that TREM2 acts downstream of CD33.

2019-06-11 | GSE132508 | GEO

Prior activation state shapes the microglia response to anti-human TREM2 in a mouse model of Alzheimer's disease

Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer’s Disease (AD) risk is associated with the TREM2R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here we tested whether TREM2 engagement by an agonistic mAb, hT2AB, designated as a surrogate ligand facilitates microglia responses in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2CV) or TREM2R47H. scRNA-seq of microglia from TREM2CV-5XFAD mice treated once with control IgG exposed trajectories representative of activated microglial populations including disease-associated microglia (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia. All of these were underrepresented in TREM2R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia transitions. Moreover, Cyc-M and IFN-R microglia were better represented in female than male TREM2CV-5XFAD mice, likely reflecting a greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished the Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In TREM2CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which microglia transitions in response to Aβ had already reached their peak. Repeated treatment with a murinized version mT2AB over a 10 days period increased brain content of chemokines in TREM2R47H-5XFAD mice, consistent with microglia expansion and shifts in gene expression patterns. Thus, the impact of hT2AB on microglia responses is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.

2020-12-08 | GSE156183 | GEO

Blood-borne macrophages contribute to Alzheimer's disease modification through a TREM2-independent pathway

Project description:Microglia and monocyte-derived macrophages (MDM) are key players in coping with Alzheimer's disease (AD). In amyloidosis mouse models, activation of microglia was found to be TREM2-dependent. Here, using Trem2-/-5xFAD mice, we assessed whether MDM act via a TREM2-dependent pathway. We adopted a treatment protocol targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, previously shown to modify AD via MDM involvement. Blocking PD-L1 in Trem2-/-5xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta (Aβ)1-42 with no effect on amyloid plaque burden. Single-cell RNA sequencing revealed that MDM, derived from both Trem2-/- and Trem2+/+5xFAD mouse brains, express a unique set of genes encoding scavenger receptors (e.g. Mrc1, Msr1). Blocking monocytes trafficking using anti-CCR2 antibody completely abrogated the cognitive improvement induced by anti-PD-L1 in Trem2-/-5xFAD mice, and similarly but to lower extent in Trem2+/+5xFAD mice. These results highlight a TREM2-independent disease-modifying activity of MDM in amyloidosis mouse model.

2021-10-24 | GSE176085 | GEO

Cortical single-cell RNA sequencing of the microglia specific TREM2 inducible mouse models in the early stage of amyloid deposition

Project description:We induced TREM2 expression at birth in our 5xFAD/TREM2 mouse models and harvested the animals at 3.5 months of age. The single cells from the cortex were isolated and subjected to the single-cell RNA seq to investigate the effects of TREM2 on microglia transcriptomic profiles in the early stage of amyloid development. Our data showed that TREM2-WT, to a lesser extent of TREM2-R47H, restricted the disease associated microglia (DAM) signature at this stage.

2020-11-11 | GSE161224 | GEO

TREM2 Gene Dosage Increase Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models

Project description:TREM2 BAC transgenic mice with elevated expression of human TREM2 in microglia under its endogenous regulation without overexpression of other TREM-like genes on the BAC were generated and crossed with 5xFAD mice, an mouse model of AD. Transcriptome and gene coexpression analyses were performed to obtain chronical view of TREM gene dosage dependent changes in the context of amyloid pathology. The results confer strong evidence that increased TREM2 alters brain transcriptome network response only in the context of a disease state and with an overall rescuing effect in 5xFAD mice.

2018-03-07 | GSE104775 | GEO

Cortical single-cell RNA sequencing of the microglia specific TREM2 inducible mouse models in the middle stage of amyloid deposition

Project description:We induced TREM2 expression at 2 months of age in our 5xFAD/TREM2 mouse models and harvested the animals at 5 months of age. The single cells from the cortex were isolated and subjected to the single-cell RNA seq to investigate the effects of TREM2 on microglia transcriptomic profiles in the middle stage of amyloid development. Our data showed that TREM2-WT induced the mTOR/EIF2 signaling pathways and restricted the disease associated microglia (DAM) signature. In contrast TREM2-R47H variant significantly upregulated the MHC class II molecules, enriched the antigen presentation pathway, and exacerbated a signature of antigen presentation contributing to enhanced amyloid pathology.

2020-11-11 | GSE161227 | GEO

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

2015-03-13 | GSE65067 | GEO

Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [scRNA-seq]

Project description:scRNA-sequencing of human xenotransplanted microglia isogenic for TREM2 after exposure to amyloid pathology

2020-09-19 | GSE158234 | GEO

Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's Disease model

Project description:TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer’s Disease (AD) risk. In mouse models of amyloid b (Ab) accumulation, defective TREM2 function affects microglial response to Ab plaques exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior and tempered glial inflammatory response. We further showed that a variant of AL002c has been given safely in a first-in-human phase I clinical trial and engages TREM2 based on CSF biomarkers. We conclude that AL002c is a promising candidate for AD therapy.

2020-05-13 | GSE150358 | GEO

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