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Expression data of iPS microglia treated with TREM2 agonist antibody

ABSTRACT: Expression data of iPS microglia treated with TREM2 agonist antibody

PROVIDER: PRJNA668377 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12804154.fastq.gz	Fastqsanger.gz
	SRR12804155.fastq.gz	Fastqsanger.gz
	SRR12804156.fastq.gz	Fastqsanger.gz
	SRR12804157.fastq.gz	Fastqsanger.gz
	SRR12804158.fastq.gz	Fastqsanger.gz

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Expression data of iPS microglia treated with TREM2 agonist antibody

Project description:Loss-of-function variants of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of developing Alzheimer's disease (AD). The mechanism through which TREM2 contributes to the disease (TREM2 activation vs inactivation) is largely unknown. Here, we analyzed changes in a gene set downstream of TREM2 to determine whether TREM2 signaling is modified by AD progression. We generated an anti-human TREM2 agonistic antibody and defined TREM2 activation in terms of the downstream expression changes induced by this antibody in microglia developed from human induced pluripotent stem cells (iPSC). Differentially expressed genes (DEGs) following TREM2 activation were compared with the gene set extracted from microglial single nuclear RNA sequencing data of patients with AD, using gene set enrichment analysis. We isolated an anti-TREM2-specific agonistic antibody, Hyb87, from anti-human TREM2 antibodies generated using binding and agonism assays, which helped us identify 300 upregulated and 251 downregulated DEGs. Pathway enrichment analysis suggested that TREM2 activation may be associated with Th2-related pathways. TREM2 activation was lower in AD microglia than in microglia from healthy subjects or patients with mild cognitive impairment. TREM2 activation also showed a significant negative correlation with disease progression. Pathway enrichment analysis of DEGs controlled by TREM2 activity indicated that TREM2 activation in AD may lead to anti-apoptotic signaling, immune response, and cytoskeletal changes in the microglia. We showed that TREM2 activation decreases with AD progression, in support of a protective role of TREM2 activation in AD. In addition, the agonistic anti-TREM2 antibody can be used to identify TREM2 activation state in AD microglia.

2021-09-15 | GSE159333 | 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 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

Transcriptional Responses to TREM2 Agonist Antibody Treatment in Cynomologus Monkey Brain [bulk RNA-seq]

Project description:In order to search for pharmacodynamic biomarkers of a TREM2 agonist antibody (Para09) in primates we performed bulk RNA-Seq on cortical tissue from cynomolgus monkeys after single IV injected doses. Changes in proliferation genes such as MKI67 were observed, as well as genes associated with glial activation, such as CHI3L1. This experiment demonstrates that our antibody induces transcriptional changes in the brain after peripheral administration.

2024-12-05 | GSE236453 | GEO

Transcriptional Responses to TREM2 Agonist Antibody Treatment in Cynomologus Monkey Brain [single nuclei RNA sequencing]

Project description:In order to search for pharmacodynamic biomarkers of a TREM2 agonist antibody (Para09) in primates we performed single nuclei RNA-Seq on cortical tissue from cynomolgus monkeys after single IV injected doses. Changes in proliferation genes such as MKI67 were observed, as well as genes associated with glial activation, such as CHI3L1. This experiment demonstrates that our antibody induces transcriptional changes in the brain after peripheral administration.

2024-12-05 | GSE241190 | GEO

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

Project description:RNA-sequencing of human iPS-microglia isogenic for TREM2 after multiple treatments

2020-09-09 | GSE157652 | GEO

Transcriptional Responses to TREM2 Agonist Antibody Treatment in Cynomologus Monkey Brain

Project description:Transcriptional Responses to TREM2 Agonist Antibody Treatment in Cynomologus Monkey Brain

| PRJNA1006736 | ENA

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

Project description:GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.

2021-07-30 | GSE181135 | GEO

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology [14 months]

2021-10-08 | GSE185510 | 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

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