Single-cell RNA-seq of sorted microglia from aged Grn KO mice [HEX000661]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE272377 | GEO | 2026/07/20
REPOSITORIES: GEO
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Project description:Previous single-cell RNA sequencing of microglia from aged WT and Grn KO mice revealed a microglial subset with transcriptomic signatures that were highly specific to Grn KO. Immunohistochemistry analysis suggested that this population was also characterized by high lipofuscin burden. In this study, we used bulk RNAseq to investigate whether these transcriptomic markers were affected by lipofuscinosis. Microglia were sorted by FACS from dissociated brain tissue of 19-month-old mice of WT or Grn KO background. Cells expressing microglial markers (CD45+/CD11b+) were selected and stratified into lipofuscin ‘low’ or ‘high’ subpopulations, based on autofluorescence. 1,000 cells were collected per sample and were processed and analyzed for bulk RNA sequencing. Results indicated a consistent upregulation of Grn KO-specific genes in microglia from the Grn KO background, which were further enriched ‘high’ vs. ‘low’ lipofuscin cells.
2026-07-20 | GSE327960 | GEO
Project description:WT or Grn knockout primary mouse microglia were treated with endolysosomal acidifier rimeporide and bulk RNA-seq was performed.
2026-07-20 | GSE272363 | GEO
Project description:Previous single-cell RNA sequencing of microglia from aged WT and Grn KO mice revealed a microglial subset with transcriptomic signatures that were highly specific to Grn KO. Further epigenetic analysis demonstrated that these signatures were likely regulated by Mitf/Tfe family transcription factors. To investigate the necessity of these transcription factors in mediating the Grn KO transcriptomic response, we turned to an experimental in vitro validation. A multiplexed CRISPR approach was used to knockout Mitf, Tfe3 and Tfeb in BMDMs from WT or Grn KO mice. 10 days post-CRISPR, bulk RNA sequencing was performed to analyze the transcriptional profiles. These profiles identified the expected enrichment of Grn KO-specific genes in BMDMs from Grn KO mouse background. Strikingly, the levels of many of these genes were reversed with knockout of Mitf, Tfe3 and Tfeb.
2026-07-20 | GSE327962 | GEO
Project description:1 year old mice were perfused and brains were dissociated. Cells were fixed, immunolabeled and FACS sorted. RNA was extracted from neuron, astrocyte, and microglial cell populations. Typical RIN=4-5 for neurons, 6-8 for astrocytes, and 5-7 for microglia. Typical RNA yields ~100ng for neurons, ~20ng for microglia, and ~10ng for astrocytes. cDNA was generated from up to 25 ng of total RNA using Nugen’s RNA-Seq method for low-input RNA samples, Ovation RNA-Seq System V2 (NuGEN). (Per manufacturers instructions, total RNA was neither depleted of rRNA nor polyA-selected.) 1 μg of sheared cDNA was taken into further processing, starting at end repair step, using Illumina’s TruSeq RNA Sample Preparation Kit v2 (Illumina). The "SAMID" sample characteristic is a sample identifier internal to Genentech. The ID of this project in Genentech's ExpressionPlot database is PRJ0007717
2017-07-06 | GSE78747 | GEO
Project description:Background: Inhalation anesthetics may trigger the hypothalamic–pituitary–adrenal (HPA) axis. FK-506 binding protein (FKBP5) is a critical factor that regulates the HPA axis and is associated with perioperative neurocognitive impairment. However, it is unclear how inhalation anesthetics affects the expression of FKBP5 in different neural cells in the brain. Methods: We used single-nucleus RNA sequencing to characterize hippocampal transcriptome profiles in the brains of aged marmosets and mice after sevoflurane anesthesia. Results: Higher levels of FKBP5 were found in the hippocampi of aged mice after sevoflurane anesthesia. Single nuclear RNA sequencing results from aged mice and marmosets showed that the increased expression of FKBP5 mainly occurred in microglia. The expression of FKBP5 in the hippocampi of aged marmosets and mice increased following long-term exposure to sevoflurane anesthesia. Additionally, the brains of these animals displayed a marked increase in the expression of FKBP5 in microglia after sevoflurane anesthesia. Conclusion: Long-term exposure to sevoflurane augments FKBP5 expression in the hippocampi of aged marmosets and mice, specifically in the microglia.
2024-10-30 | GSE234493 | GEO
Project description:Age-dependent alterations in microglia behavior have been implicated in neurodegeneration and CNS injuries. Here, we compared the transcriptional profiles of young versus aged microglia during stroke recovery. CD45intermediateCD11b+ microglia were FACS-isolated from the brains of young (10-week-old) and aged (18-month-old) male mice 14 days after distal middle cerebral artery occlusion (dMCAO) or sham operation and subjected to RNA-sequencing analysis. Functional groups enriched in young microglia are indicative of upregulation in cell movement, cell interactions, inflammatory responses and angiogenesis, while aged microglia exhibited a reduction or no change in these features. We confirmed reduced chemoattractive capacities of aged microglia toward ischemic brain tissue in organotypic slide co-cultures, and delayed accumulation of aged microglia around dead neurons injected into the striatum in vivo. In addition, aging is associated with an overall failure to increase the expression of microglial genes involved in cell-cell interactions, such as CXCL10. Finally, impaired upregulation of pro-angiogenic genes in aged microglia was associated with a decline in neovascularization in aged mice compared to young mice after dMCAO. This study provides a new resource to understand the mechanisms underlying microglial alterations in the aged brain milieu and sheds light on new strategies to improve microglial functions in aged stroke victims.
2020-01-31 | GSE142361 | GEO
Project description:Heterozygous mutations in the granulin (GRN) gene result in haploinsufficiency of the progranulin (PGRN) protein, a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in the TMEM106B gene have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants are associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. In vitro, TMEM106B deletion did not reverse transcriptomic and proteomic profiles in GRN-deficient microglia, with the exception of a small set of immune-related proteins in the NF-κB pathway. In vivo, neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated gene expression in sorted microglia, lipid abnormalities, or histopathology in Grn knock-out mice. Furthermore, Tmem106b reduction with antisense oligonucleotide (ASO) treatment was poorly tolerated in Grn knock-out mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTLD-GRN.
2023-11-15 | GSE237106 | GEO
Project description:Heterozygous mutations in the granulin (GRN) gene result in haploinsufficiency of the progranulin (PGRN) protein, a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in the TMEM106B gene have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants are associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. In vitro, TMEM106B deletion did not reverse transcriptomic and proteomic profiles in GRN-deficient microglia, with the exception of a small set of immune-related proteins in the NF-κB pathway. In vivo, neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated gene expression in sorted microglia, lipid abnormalities, or histopathology in Grn knock-out mice. Furthermore, Tmem106b reduction with antisense oligonucleotide (ASO) treatment was poorly tolerated in Grn knock-out mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTLD-GRN.
2023-11-15 | GSE237105 | GEO
Project description:Heterozygous mutations in the granulin (GRN) gene result in haploinsufficiency of the progranulin (PGRN) protein, a leading cause of frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Polymorphisms in the TMEM106B gene have been associated with disease risk in GRN mutation carriers and protective TMEM106B variants are associated with reduced levels of TMEM106B, suggesting that lowering TMEM106B might be therapeutic in the context of FTLD. Here we tested the impact of full deletion and partial reduction of TMEM106B in mouse and iPSC-derived human cell models of GRN deficiency. In vitro, TMEM106B deletion did not reverse transcriptomic and proteomic profiles in GRN-deficient microglia, with the exception of a small set of immune-related proteins in the NF-κB pathway. In vivo, neither homozygous nor heterozygous Tmem106b deletion normalized disease-associated gene expression in sorted microglia, lipid abnormalities, or histopathology in Grn knock-out mice. Furthermore, Tmem106b reduction with antisense oligonucleotide (ASO) treatment was poorly tolerated in Grn knock-out mice. These data provide novel insight into TMEM106B and GRN function in microglia cells but do not support lowering TMEM106B levels as a viable therapeutic strategy for treating FTLD-GRN.
2023-11-15 | GSE237104 | GEO
Project description:Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood–brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.
2022-06-03 | GSE163122 | GEO