Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA302422 | ENA |
REPOSITORIES: ENA
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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:Transcriptomic profiling of mouse brain in old progranulin deficient mice with a complete loss of progranulin (PGRN KO), with restoration of neuronal progranulin (NesGrnOE-KOBG), in progranulin-EGFL7 double deficient mice (EGFL7-PGRNdko) and floxed control mice (Grnflfl) Genetic progranulin deficiency in humans causes Frontotemporal Dementia (FTD). Progranulin knockout mice (PGRNko) are a model for the disease albeit cognitive impairment in mice is subtle. The predominant FTD-phenotype in mice are hyperactivity, sugar craving, compulsiveness, skin lesions owing to exessive grooming and general health issues in old mice such as anal prolaps. Progranulin in primarily expressed in neurons and in myeloid derived immune cells including microglia. Progranulin deficient microglia are neuron-aggressive and are believed to contribute to excessive synaptic pruning. It is not known if progranulin that is normally neurotrophic and keeps microglia in a neuron-supportive phenotype has to come from within microglia or is a progranulin-signal from neurons to microglia. To dissect out the differential contribution we generated mice which express progranulin in neurons via Nestin-driven restoration of progranulin expression in a progranulin knockout background. In addition we assessed additional deletion of EGFL7, which behaves as progranulin competitor for binding/activation of NOTCH receptors. Hence, this study describes and compared the transcriptome of old mice in four mouse lines: full progranulin knockout (PGRNko), neuronal resoration of PGRN on a knockout background (NesGrnOE-koBG), progranulin & EGFL7 double deletion (EGFL7-PGRNdko) and floxed progranulin control mice (Grn flfl). Mice were 60-70 weeks old at the the time of tissue collection. Total RNA was extracted with Qiagen RNAeasy micro-kits and sequencing librariers were prepared by Novogene according to standard protocols for mRNA sequencing. RNA seq was done on Illumina NovaSeq 6000. The sequence alignment was done with standard proceduers including quality filtering and adapter trimming with Qiagen's CLC Genomic Workbench. The TMM (trimmed mean od M-values) algorithm was used for read normalization. Total reads, RPKM and TPM are also provided in "Processed data" files.
2026-03-11 | GSE273083 | GEO
Project description:Microglia-mediated neuroinflammation has been identified as pathogenic in autism spectrum disorders (ASD). Pathogenic factors for microglial activation remain unclear. In our study, we discovered that complement C4b is highly expressed in the prefrontal cortex (PFC) neurons with SETDB1 deficiency, a high-risk gene of ASD, or by maternal inflammation (MI). Exposure to C4b led microglia to perform excessive synaptic pruning, which in turn manifested ASD-like phenotypes. Furthermore, we observed that removing microglia could improve synaptic functions, while the complete knockout of C4b could rescue all observed autistic phenotypes. The expression of C4b was contingent upon RNA-DNA hybrids formed by the reactivation of Endogenous Retroviruses (ERVs).Interestingly, the pharmacological reversal of this retrotranscriptional process with FDA-approved HIV medications significantly reduced C4b levels and ameliorated the symptoms of ASD. Our findings illuminate the pivotal role of C4b in microglia-driven synaptic pruning linked to ASD and suggest that targeting ERV reactivation could be a promising therapeutic strategy with existing FDA-approved HIV drugs.
2026-02-24 | GSE275174 | GEO
Project description:Microglia-mediated neuroinflammation has been identified as pathogenic in autism spectrum disorders (ASD). Pathogenic factors for microglial activation remain unclear. In our study, we discovered that complement C4b is highly expressed in the prefrontal cortex (PFC) neurons with SETDB1 deficiency, a high-risk gene of ASD, or by maternal inflammation (MI). Exposure to C4b led microglia to perform excessive synaptic pruning, which in turn manifested ASD-like phenotypes. Furthermore, we observed that removing microglia could improve synaptic functions, while the complete knockout of C4b could rescue all observed autistic phenotypes. The expression of C4b was contingent upon RNA-DNA hybrids formed by the reactivation of Endogenous Retroviruses (ERVs). Interestingly, the pharmacological reversal of this retrotranscriptional process with FDA-approved HIV medications significantly reduced C4b levels and ameliorated the symptoms of ASD. Our findings illuminate the pivotal role of C4b in microglia-driven synaptic pruning linked to ASD and suggest that targeting ERV reactivation could be a promising therapeutic strategy with existing FDA-approved HIV drugs.
2026-02-24 | GSE275136 | 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