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GPR34 senses demyelination to promote neuroinflammation and cognition impairment in Alzheimer's disease

ABSTRACT: GPR34 senses demyelination to promote neuroinflammation and cognition impairment in Alzheimer's disease

PROVIDER: PRJNA892590 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21986228_1.fastq.gz	Fastqsanger.gz
	SRR21986228_2.fastq.gz	Fastqsanger.gz
	SRR21986229_1.fastq.gz	Fastqsanger.gz
	SRR21986229_2.fastq.gz	Fastqsanger.gz
	SRR21986230_1.fastq.gz	Fastqsanger.gz

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GPR34 senses demyelination to promote neuroinflammation and cognition impairment in Alzheimer's disease

Project description:Sterile neuroinflammation initiated by damage-associated molecular patterns (DAMPs) has been regarded as an important driver in Alzheimer's disease (AD) and can occur prior or independently of the deposition of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles (NFTs). Genetic ablation or pharmacological inhibition of GPR34 reduced microglia activation, Aβ deposition and cognition impairment. Moreover, GPR34 inhibition prevented aging associated neuroinflammation and cognition impairment without the presence of Aβ plaques.

2025-02-05 | GSE216209 | GEO

GPR34 senses myelin debris to promote neuroinflammation and pathology

Project description:Sterile neuroinflammation is a major driver of multiple neurological diseases. Myelin debris, which is released from the damaged myelin sheaths during demyelination, can act as an inflammatory stimulus to promote sterile inflammation and neurological pathologies, but the mechanism is poorly understood. Here, we show that lysophosphatidylserine (LysoPS)-GPR34 axis plays a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation. Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS. Both myelin debris and LysoPS promoted microglia to produce IL-1and IL-6 via GPR34 and its downstream PI3K-AKT and ERK signaling. In vivo, LysoPS production and GPR34 signaling were found to be essential for neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke. Importantly, pharmacologic blockade of GPR34 showed potential therapeutic effects on these disease models. Thus, our results identify GPR34 as a key receptor to sense myelin debris and promote neuroinflammation, and suggest it as a potential target for demyelination-associated diseases.

2025-01-30 | GSE195741 | GEO

GPR34 senses myelin debris to promote neuroinflammation and pathology

Project description:GPR34 senses myelin debris to promote neuroinflammation and pathology

| PRJNA802043 | ENA

Investigating GPR34 expression regulation using whole transcriptome sequencing of spleens and dendritic cells from wildtype and GPR34 knockout mice

Project description:Naive spleens as well as naive and LPS-treated dendritic cells from wildtype and GPR34-/- mice were sequenced to integrate expression profiles with protein interaction networks and find functional modules that are affected by GPR34 Expression profiles of dendritic cells and whole spleens were generated using Illumina HiSeq 2500/ Illumina HiScan

2016-03-02 | E-GEOD-68155 | biostudies-arrayexpress

Investigating GPR34 expression regulation using whole transcriptome sequencing of spleens and dendritic cells from wildtype and GPR34 knockout mice

2016-03-02 | GSE68155 | GEO

Therapeutic reactivation of hippocampal progenitors reverses cognition decline in progressive brain demyelination

Project description:Therapeutic reactivation of hippocampal progenitors reverses cognition decline in progressive brain demyelination

| PRJNA1215377 | ENA

Therapeutic reactivation of hippocampal progenitors reverses cognition decline in progressive brain demyelination

Project description:Chronic brain demyelination and neurodegeneration are pathological hallmarks of progressive multiple sclerosis (MS) that underlie cognitive impairments. Neural precursor cells (NPCs) that reside in the hippocampus support cognition through adult neurogenesis. However, with MS chronicity, hippocampal neurogenesis declines that results in memory and learning impairments. Currently, the underlying mechanisms that drive NPC senescence in chronic MS are largely unknown. Here, we have linked downregulation of Neuregulin-1beta 1 (Nrg-1β1) to hippocampal neurodegeneration, neurogenic decline and memory impairment in mice with chronic brain demyelination. Nrg-1β1 is a key factor for neural differentiation that we previously reported its downregulation in chronic human MS lesions. Here, extensive in vivo and in vitro characterizations revealed that therapeutic restoration of Nrg-1β1 can reactivate NPCs and foster hippocampal repair by neurogenesis, synapse reassembly and remyelination that reverses memory impairments. Transcriptomics of NPC progenies confirmed upregulation of genes associated with myelination, synaptic resilience, and cellular homeostasis, underscoring the potential of Nrg-1β1 in activating regenerative mechanisms within the chronically demyelinated hippocampus. Moreover, in comparison with Siponimod, a leading disease modifying therapy for secondary progressive MS, Nrg1β1 treatment achieved multifaceted and greater reparative effects. These new findings introduce Nrg1β1 as a disease relevant candidate with promising therapeutic potential for progressive MS.

2026-03-24 | GSE287967 | GEO

GPR34 regulation of disease-associated microglial states in mice

Project description:We investigated the role of the microglia-enriched G protein–coupled receptor GPR34 in regulating cell states for microglia and other cell types under physiological and disease conditions using single-cell RNA sequencing (scRNA-seq) and single-nuclei RNA sequencing (snRNA-seq). Microglia isolated from Gpr34 knockout (KO) and wild-type mice, with or without the 5xFAD Alzheimer’s disease background, were profiled to assess transcriptional changes associated with GPR34 loss, as were other cell types in the hippocampus. Our findings indicate that GPR34 plays a critical role in maintaining microglial homeostasis and restraining disease-associated transcriptional responses in vivo.

2026-04-09 | GSE327428 | GEO

GPR34 regulation of disease-associated microglial states in iMGL

Project description:GPR34 is a microglia-enriched GPCR whose expression is downregulated under several disease conditions, including Alzheimer’s disease (AD) and multiple sclerosis (MS). Despite this, its function is poorly understood in normal or disease conditions, as is its contribution to disease-related microglia states. Using RNA-sequencing, we find that microglia from global Gpr34 knockout (KO) mouse brains exhibited transcriptional shifts toward disease-associated microglia (DAM) and inflammatory profiles, partially mirroring the microglial phenotype seen in 5xFAD AD model mice. Notably, when Gpr34 KO mice were crossed with 5xFAD mice, DAM transcriptional profiles and glial pathology were further exacerbated despite the already robust DAM signature driven by amyloidosis. This occurred without affecting amyloid plaque burden. In human stem cell-derived microglia (iMGLs), GPR34 KO strongly reduced calcium (Ca²⁺) and phosphorylated ERK (pERK) signaling in response to known GPR34 agonists, including lyso-phosphatidylserine (lysoPS) and myelin, and caused transcriptional alterations linked to immune regulation and cell proliferation. Interestingly, GPR34 loss selectively impaired phagocytosis of myelin but not amyloid-β or E. coli. Furthermore, GRP34 KO diminished, but did not abolish, the transcriptional response elicited by myelin. Together, these findings suggest that GPR34 is important for maintaining microglia homeostasis, mediating phagocytosis of and transcriptional response to myelin, and restraining microglial response to neurodegenerative disease conditions.

2026-04-10 | GSE327711 | GEO

Impaired removal of dying brain cells by microglia in GPR34 deficient mice

Project description:GPR34, a G protein coupled receptor present selectively in microglia and other myeloid cells, is highly expressed in homeostatic microglia but is downregulated in disease associated microglia such as are found in Alzheimer’s disease brain. However, little is known about GPR34’s role in microglia function or brain development. Here, we studied Gpr34 knockout (KO) mice at postnatal 18-day (18 d) and 3 months (3 mo) age. In the brains of 18 d GPR34 KO mice, there were elevated numbers of neurons, oligodendrocytes and microglia, many of which were IHC-positive for cell death markers cleaved-caspase 3, phospho-RIP3, or annexin V. There was no increase in cell death markers or in steady state numbers of neurons, oligos and microglia at 3 months, indicating that GPR34-independent mechanisms are able to compensate during brain maturation. Based on RNA sequencing analysis and phagocytosis functional assays, as well as computational modeling, we provide evidence that Gpr34 KO microglia have deficiencies in chemotaxis, but not phagocytic efficiency, which leads to a slower clearance of dead cells from the developing brain. Collectively, these results indicate that Gpr34 is required for microglia to clear dead or dying cells.

2026-01-22 | GSE317348 | GEO

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