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Opposite microglial activation stages upon loss of PGRN result in reduced cerebral glucose metabolism

ABSTRACT: Opposite microglial activation stages upon loss of PGRN result in reduced cerebral glucose metabolism

PROVIDER: PRJNA533226 | ENA |

REPOSITORIES: ENA

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Opposite microglial activation stages upon loss of PGRN result in reduced cerebral glucose metabolism

Project description:Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss-of-function. We have now isolated microglia from Grn–/– mice and compared their transcriptomes to those of Trem2–/– mice. Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn–/– mice showed a reciprocal activation of the MGnD molecular signature and suppression of genes characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro-2-deoxy-D-glucose)-µPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.

2019-04-18 | GSE129709 | GEO

Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism.

Project description:Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn-/- mice and compared their transcriptomes to those of Trem2-/-mice Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn-/- mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro-2-deoxy-d-glucose)-μPET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.

| S-EPMC6554672 | biostudies-literature

Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism

Project description:Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and Frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss-of-function. We have now isolated microglia from Grn-/- mice and compared their transcriptomes to those of Trem2-/- mice. Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn-/- mice showed a reciprocal activation of the MGnD molecular signature and suppression of genes characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro-2-deoxy-D-glucose)-?PET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.

| S-SCDT-EMM-2018-09711 | biostudies-other

PGRN-RIKEN Mayo Breast Cancer

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Dioscorea opposite

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PGRN-RIKEN Mayo-NSABP Prevention Study

Project description:PGRN-RIKEN Mayo-NSABP Prevention Study

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PGRN: Cholesterol and Pharmacogenetics Study (CAP)

Project description:PGRN: Cholesterol and Pharmacogenetics Study (CAP)

| PRJNA156877 | ENA

Opposite functions of microglial and macrophagial TNFR2 in EAE pathogenesis: the good versus the bad.

Project description:In MS pathophysiology, soluble tumor necrosis factor (TNF) has been attributed detrimental functions, whereas transmembrane TNF promotes neurorepair primarily by activating TNF receptor 2 (TNFR2). Here we investigate the role of TNFR2 in microglia and peripheral monocyte/macrophages in EAE using novel cell-specific conditional knockouts. We show that microglial TNFR2 ablation leads to early onset of EAE, with increased CNS leucocyte infiltration, T cell activation, and demyelination. TNFR2-ablated microglia shows a more pro-inflammatory phenotype, with dysregulation of genes controlling innate immunity and host defense. Conversely, monocyte/macrophagial TNFR2 ablation results in EAE suppression, with impaired peripheral T cell activation. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease, and monocyte/macrophagial TNFR2 driving immune activation and EAE initiation. This needs to be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases to which both populations are key contributors.

2016-11-21 | GSE78082 | GEO

Next-generation sequencing analysis of wild-type and PGRN-/- mouse neutrophils challenged with Candida albicans [RNA-seq]

Project description:To investigate the effect of Progranulin on neutrophils phagocytosis and killing of Candida albicans, we designed RNA-Seq analysis of wild-type and PGRN-/- neutrophils challenged with Candida albicans in vitro at one time point.

2022-09-13 | GSE201166 | GEO

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