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BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer's disease and related dementias

ABSTRACT: BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer's disease and related dementias

PROVIDER: PRJNA976728 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR24751223_1.fastq.gz	Fastqsanger.gz
	SRR24751223_2.fastq.gz	Fastqsanger.gz
	SRR24751224_1.fastq.gz	Fastqsanger.gz
	SRR24751224_2.fastq.gz	Fastqsanger.gz

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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

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

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BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer's disease and related dementias

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

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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 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.

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2021-10-24 | GSE176085 | 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

Acute TREM2 Blockade Impairs Remyelination by Reducing MAFB-High Microglia

Project description:We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor found on microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the Trem2 gene in mice impairs remyelination. Here we blocked TREM2 function acutely with an antibody during both the demyelination and remyelination phases and analyzed the impact of the antibody on myelination and gene expression in single cells. We found that blocking TREM2 depleted a specific population of microglia characterized by high expression of the transcription factor MAFB during remyelination. These MAFB-high microglia were crucial for myelin repair, and their depletion led to impairment of myelinating oligodendrocytes. Importantly, we identified MAFB+ microglia in acute and acute-chronic brain lesions from individuals with multiple sclerosis (MS), but not in inactive lesions. We conclude that TREM2 is essential for maintaining a population of MAFB-high microglia that are critical for myelin repair. This finding has important implications for understanding demyelinating diseases like MS and suggests that stimulating TREM2 could be a potential therapeutic strategy.

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