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Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [7 months]

ABSTRACT: Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [7 months]

PROVIDER: PRJNA590042 | ENA |

REPOSITORIES: ENA

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Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [15 months]

Project description:Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [15 months]

| PRJNA589621 | ENA

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [7 months]

Project description:Glia have been implicated in Alzheimer’s disease (AD) pathogenesis. Variants of the microglia receptor TREM2 increase AD risk and activation of “disease-associated microglia” (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene expression changes associated with AD pathology and TREM2 in 5XFAD mice and human AD by snRNA-seq. We confirmed the presence of Trem2-dependent DAM and identified a novel Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less palpable in TREM2 R47H and R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

2019-12-31 | GSE140510 | GEO

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease [15 months]

2019-12-31 | GSE140399 | GEO

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease

Project description:Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and -independent cellular responses in Alzheimer’s disease

| PRJNA590041 | ENA

Subtle changes in brain expression modules in Alzheimer’s disease TREM2 carriers compared to non-carriers

Project description:Background: Rare heterozygous coding variants with a large effect on the risk of developing late-onset Alzheimer's disease (similar to ApoE4, OR 2.90-5.05) have been identified in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene. However, little is known about the mechanisms through which Trem2 maladjustment may lead to AD Methods: We performed differential expression and co-expression network analysis on samples obtained from 5 (mainly 2) brain areas from individuals carrying the TREM2 variant known to increase the risk of Alzheimer’s and others using RNA-Seq to obtain a systems level view of the effects of the TREM2 mutation Results: The absence of Trem2 has a stronger effect at an earlier age with the number of differential expressed (DE) genes being 17-fold greater at 4 months than at 8 months in cortex. By integrating DE genes and network analysis we discovered gene clusters associated with the disruption of blood vessel formation at 4 months of age and protein targeting primarily affecting the hippocampus at 8 months. Further integration of cell type and ontology information revealed a large disruption of a gene module enriched for endothelial cell markers coinciding with the module enriched for neuron cell markers having weaker connections to modules with oligodendrocyte and astrocyte identities. The module with neuronal identity has decreased expression only in the KO where it has closer association with a new module enriched for phagocytic functions Conclusions: Combining gene co-expression and differential expression analysis on brains of carriers of TREM2 mutations we demonstrate that the presence of damaging TREM2 mutation produce subtle disruptions.

2025-10-04 | GSE140841 | GEO

Single-nucleus RNA sequencing of dorsolateral prefrontal cortex from normal, pathological aging, and Alzheimer’s disease human brains

Project description:We performed single-nucleus RNA sequencing of the dorsolateral prefrontal cortex from 15 normal, pathological aging, and Alzheimer’s disease human brains that varied by APOE and TREM2 genotype to analyze cell-type specific transcriptomic changes across the range of Alzheimer’s disease pathology and genetic risk factors.

2023-10-02 | GSE243292 | GEO

The Gain-of-Function TREM2-T96K Mutation Increases Risk for Alzheimer’s Disease by Impairing Microglial Function

Project description:The aim of this study is to characterize the underlying molecular mechanisms of the gain-of-function Trem2T96K mutation in Alzheimer’s disease (AD) pathogenesis by using the constitutive Trem2T96K knock-in mouse crossed to the 5xFAD mouse model of AD. Gene expression analyses were performed on microglial cells isolated from male and female Trem2+/+ (WT), 5xFAD;Trem2+/+, 5xFAD;Trem2T96K/+, and 5xFAD;Trem2T96K/T96K mice at 8 months of age to analyze the impact of the Trem2T96K mutation on the transcriptome of microglia in the setting of neuroinflammation (i.e. in the 5xFAD brain). The results revealed that Trem2T96K reprogrammed microglial gene expression and downregulated signaling pathways related to microglial function, specifically, in female 5xFAD mice.

2025-09-17 | GSE307564 | GEO

PLCG2 modulates TREM2 expression and signaling in response to Alzheimer’s disease pathology 

Project description:Phospholipase C gamma 2 (PLCG2) is an intracellular effector of microglial cell surface receptors, including TREM2. Variants which alter PLCG2 activity impact Alzheimer’s disease (AD) risk, but the effects of PLCG2 deficiency in AD remain unclear.

2025-05-14 | GSE291648 | GEO

PLCG2 Regulates Divergent Microglial Functions via TREM2-Dependent and -Independent Signaling

Project description:We use genetically engineered human iPSC-derived microglia-like cells (iMG) to show that TREM2 signals through PLCγ2 to mediate cell survival, phagocytosis, and lipid metabolism following myelin challenge. Loss of TREM2 or PLCγ2 signaling leads to a shared signature of transcriptional dysregulation that underlies these phenotypes. However, PLCγ2 also signals downstream of Toll-like receptors to mediate inflammatory responses in a TREM2-independent manner. Therefore, PLCγ2 activity regulates divergent microglial functions via distinct TREM2-dependent and -independent signaling and may be involved in the transition to a microglial state associated with neurodegenerative disease.

2020-05-24 | GSE144120 | GEO

CSF and brain proteomics of Trem2-mKate2 KI/wt.APPSAA/SAA.hTfR KI/KI mice

Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer’s disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse model. Experimental mice expressed the reporter heterozygous while AppSAA and the hTfR knock-in were homozygous (Trem2-mKate2 KI/wt.APPSAA/SAA.hTfR KI/KI) and were treated with the antibody transport vehicle coupled TREM2 agonist antibody ATV:4D9. After the treatment CSF and brain samples were colleceted for proteomics analyses.

2025-12-08 | PXD065438 | Pride

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