Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA302422 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency. Gene expression study in multiple brain regions from a mouse model of progranulin deficiency Please note that 9 outlier samples were excluded from data analysis. Therefore, there are 326 raw data columns (i.e. 163 samples) in the non_normalized data matrix while 154 samples are represented here.
2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress
Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency.
2016-03-31 | GSE75083 | GEO
Project description:Learning and memory capability always decline with age in healthy people, and synapse loss may be an important factor contributing to this reduction. The complement pathway plays a crucial role in synaptic pruning during normal brain development, and the abnormal activation of the classical complement cascade is involved in the pathogenesis of certain neurological disorders. However, none of the past studies elucidated the effects of complement proteins in the aging of the nervous system. Here, we performed transcriptome sequencing in multiple tissues of mice at different ages in an attempt to find important regulators during aging. Our results show that the expression of complement protein C4 in the mouse brain increases with aging. In addition, we constructed different neuronal aging models for transcriptome analysis to identify the regulatory pathways upstream of complement C4, and explored the possible mechanism of complement C4 involved in synapse pruning by co-culture or immunofluorescence methods. This further demonstrates that complement C4 is a potential marker of aging. These findings suggest that NF-κB signaling pathway may contribute to age dependent complement C4 increase, which in turn affect learning and memory function via neuronal synaptic pruning regulation.
2025-07-01 | GSE285864 | GEO
Project description:Learning and memory capability always decline with age in healthy people, and synapse loss may be an important factor contributing to this reduction. The complement pathway plays a crucial role in synaptic pruning during normal brain development, and the abnormal activation of the classical complement cascade is involved in the pathogenesis of certain neurological disorders. However, none of the past studies elucidated the effects of complement proteins in the aging of the nervous system. Here, we performed transcriptome sequencing in multiple tissues of mice at different ages in an attempt to find important regulators during aging. Our results show that the expression of complement protein C4 in the mouse brain increases with aging. In addition, we constructed different neuronal aging models for transcriptome analysis to identify the regulatory pathways upstream of complement C4, and explored the possible mechanism of complement C4 involved in synapse pruning by co-culture or immunofluorescence methods. This further demonstrates that complement C4 is a potential marker of aging. These findings suggest that NF-κB signaling pathway may contribute to age dependent complement C4 increase, which in turn affect learning and memory function via neuronal synaptic pruning regulation.
2025-07-01 | GSE285863 | GEO
Project description:Up to 75% of systematic lupus erythematosus (SLE) patients experience neuropsychiatric (NP) symptoms, called neuropsychiatric SLE (NPSLE), yet the underlying mechanisms remain elusive. Complement cascades mediate synaptic pruning by microglia during early postnatal brain development. The process in NPSLE remains unclear. Here, we show that complement-coordinated elimination of synaptic terminals participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We elucidated that lupus mice developed increased anxiety-like behaviors and persistent phagocytic microglia reactivation before overt peripheral lupus pathology. Microglial engulfment of synapses explained behavioral disorders. We further determined that neuronal Nr4a1 signaling was essential for attracting C1q synaptic deposition then apposition of phagocytic microglia, ensuing synaptic loss and neurological disease. Minocycline-deactivated microglia, antibody-blocked C1q, or neuronal Nr4a1 restore protected lupus mice from synapse loss and NP manifestations. Our findings revealed an active role of neurons in coordinating microglia-mediated synaptic loss and highlight neuronal Nr4a1 and C1q as critical components amenable to pharmacological intervention.
2022-02-23 | GSE154288 | GEO
Project description:Recent studies reveal that microglia modulate synaptic transmission by direct synaptic pruning. Microglia reactivation is a crucial mechanism of central sensitization in neuropathic pain, yet the exact changes of microglia during the development of neuropathic pain and its interaction with the spinal inhibitory circuits remains unclear. In this work, single-cell sequencing delineates temporal changes in spinal microglia and identifies a specific type of microglia as the subpopulation mediating synaptic pruning. We found that peripheral nerve injury induced the transition of spinal microglia from a pro-inflammatory to a “pruning” state, resulting in pain hypersensitivity by spinal disinhibition.
2024-10-24 | GSE246288 | GEO
Project description:This study corresponds to the single nucleus RNA sequencing (snRNAseq) analysis done as part of the manuscript "Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system" by Matera et al. INPP5D, which encodes the lipid phosphatase SHIP1, is one of the most common genes associated with the risk of Alzheimer’s disease and is enriched in microglia in the central nervous system. SHIP1 has been found to be highly expressed in plaque-associated microglia. However, how it regulates microglial function and influences brain physiology has been poorly investigated. In this study, we generated a snRNAseq dataset from the hippocampi of wildtype (WT) and conditional SHIP1 knockout (KO) mice at postnatal day 15. By predicting cell-cell communication, we found decreased neuronal interactions in KO mice, in line with results of synaptic loss in the rest of the manuscript.
2025-04-28 | GSE264452 | GEO
Project description:INPP5D, which encodes the lipid phosphatase SHIP1, is one of the most common genes associated with the risk of Alzheimer’s disease and is enriched in microglia in the central nervous system. SHIP1 has been found to be highly expressed in plaque-associated microglia. However, how it regulates microglial function and influences brain physiology has been poorly investigated. Here we show that SHIP1 is not only enriched in microglia associated with amyloid beta plaques, but also in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that conditional knockout mice lacking microglial SHIP1 (cKO) display increased complement and synapse loss in the early postnatal brain. Additionally, SHIP1 KO microglia show reduced morphological complexity, altered transcriptional signatures, and abnormal synaptic pruning, which is dependent on the complement system. Single nucleus RNA-sequencing analysis of the entire hippocampus confirmed decreased interaction for synaptic structure-related pathways in both excitatory and inhibitory neurons. Importantly, cKO mice show cognitive defects in adulthood only when microglial SHIP1 is depleted at early postnatal days, but not when depleted at later stages. Finally, using CRISPR/Cas9 we generated human iPSC-derived microglia lacking SHIP1, and validated the increased engulfment of synaptic structures. Altogether, these findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling through the complement system in the early postnatal brain. Disrupting this process has lasting behavioral effects and may provide a link to vulnerability to neurodegeneration.
2024-12-04 | PXD052118 | Pride
Project description:Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system
| PRJNA1171307 | ENA
Project description:Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system
| PRJNA1116096 | ENA