Deletion of the Alzheimer’s Disease-associated CD33 results in increased phagocytosis, oxidative burst and inflammation
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ABSTRACT:
PROVIDER: PRJNA650315 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12371410.fastq.gz | Fastqsanger.gz | |||
| SRR12371411.fastq.gz | Fastqsanger.gz | |||
| SRR12371412.fastq.gz | Fastqsanger.gz | |||
| SRR12371413.fastq.gz | Fastqsanger.gz | |||
| SRR12371414.fastq.gz | Fastqsanger.gz |
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Project description:In this study, wild type and CD33 knockout human THP1 macrophages were treated with control shRNA or shRNA against the CD33 signaling-associated protein tyrosine phosphatase PTPN6 and analyzed by mRNA sequencing. Whole genome transcriptome analysis showed that knockout of CD33 as well as knockdown of PTPN6 led to constitutive activation of inflammation-related pathways. On the other hand, PTPN6 knockdown was associated with changes in cell cycle and mitosis-related pathways in a CD33-deficient background.
2021-01-31 | GSE155567 | GEO
Project description:Background: CD33 is genetically linked to Alzheimer’s disease (AD) susceptibility through differential expression of isoforms in microglia. The role of the human CD33 short isoform (hCD33m), preferentially encoded by an AD-protective CD33 allele (rs12459419T), is unknown. Here, we test whether hCD33m represents a loss-of-function or gain-of-function variant. Results: In both primary microglia and U937 cells, we find that hCD33m enhances phagocytosis. This contrasts with the human CD33 long isoform (hCD33M) that represses phagocytosis, as previously demonstrated. As revealed by scRNAseq, hCD33m+ microglia are enriched in a cluster of cells defined by an upregulated expression and gene regulatory network of immediate early genes, which was further validated within microglia in situ. Using a new hCD33m-specific antibody enabled hCD33m expression to be examined, demonstrating a preference for an intracellular location. Moreover, this newly discovered gain-of-function role for hCD33m is dependent on its cytoplasmic signaling motifs, dominant over hCD33M, and not due to loss of glycan ligand binding. Conclusions: These results provide strong support that hCD33m represents a gain-of-function isoform and offers insight into what it may take to therapeutically capture the AD-protective CD33 allele. We have developed two models to test the role of hCD33m. The first is a new strain of transgenic mice expressing hCD33m in the microglial cell lineage. The second is U937 cells where the CD33 gene was disrupted by CRISPR/Cas9 and complemented with different variants of hCD33. Primary microglia and U937 cells were tested in phagocytosis assays and single cell RNA sequencing (scRNAseq) was carried out on the primary microglia. Furthermore, a new monoclonal antibody was developed to detect hCD33m more efficiently.
2021-04-21 | GSE172525 | GEO
Project description:Background: CD33 is genetically linked to Alzheimer’s disease (AD) susceptibility through differential expression of isoforms in microglia. The role of the human CD33 short isoform (hCD33m), preferentially encoded by an AD-protective CD33 allele (rs12459419T), is unknown. Here, we test whether hCD33m represents a loss-of-function or gain-of-function variant. Results: In both primary microglia and U937 cells, we find that hCD33m enhances phagocytosis. This contrasts with the human CD33 long isoform (hCD33M) that represses phagocytosis, as previously demonstrated. As revealed by scRNAseq, hCD33m+ microglia are enriched in a cluster of cells defined by an upregulated expression and gene regulatory network of immediate early genes, which was further validated within microglia in situ. Using a new hCD33m-specific antibody enabled hCD33m expression to be examined, demonstrating a preference for an intracellular location. Moreover, this newly discovered gain-of-function role for hCD33m is dependent on its cytoplasmic signaling motifs, dominant over hCD33M, and not due to loss of glycan ligand binding. Conclusions: These results provide strong support that hCD33m represents a gain-of-function isoform and offers insight into what it may take to therapeutically capture the AD-protective CD33 allele. We have developed two models to test the role of hCD33m. The first is a new strain of transgenic mice expressing hCD33m in the microglial cell lineage. The second is U937 cells where the CD33 gene was disrupted by CRISPR/Cas9 and complemented with different variants of hCD33. Primary microglia and U937 cells were tested in phagocytosis assays and single cell RNA sequencing (scRNAseq) was carried out on the primary microglia. Furthermore, a new monoclonal antibody was developed to detect hCD33m more efficiently.
2021-04-21 | GSE172527 | GEO
Project description:CD33-/- and/or TREM2-/- mice were crossed with the 5xFAD mouse model of Alzheimer’s disease to generate single and double CD33/TREM2 knock-out mice on 5xFAD background. Transcriptome and gene expression analyses were performed to analyze the impact of CD33 and/or TREM2 knock-out on the transcriptome of microglia in the context of amyloid pathology. The results revealed that CD33 and/or TREM2 knock-out reprogrammed microglial gene expression signatures in 5xFAD mice in an age-dependent manner. Differential gene expression in 5xFAD;CD33-/- microglia depended on the presence of TREM2. These data suggest that TREM2 acts downstream of CD33.
2019-06-11 | GSE132508 | GEO
Project description:Rattus norvegicus Cd33, CD33 molecule [Source:RGD Symbol;Acc:1596020], is differentially expressed in 23 experiment(s);
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Project description:Rattus norvegicus Cd33, CD33 molecule [Source:RGD Symbol;Acc:1596020], is expressed in 5 baseline experiment(s);
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Project description:Macaca mulatta CD33, CD33 molecule [Source:VGNC Symbol;Acc:VGNC:81368], is expressed in 3 baseline experiment(s);
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Project description:Homo sapiens CD33, CD33 molecule [Source:HGNC Symbol;Acc:HGNC:1659], is differentially expressed in 124 experiment(s);
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Project description:Homo sapiens CD33, CD33 molecule [Source:HGNC Symbol;Acc:HGNC:1659], is expressed in 29 baseline experiment(s);
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Project description:Mus musculus Cd33, CD33 antigen [Source:MGI Symbol;Acc:MGI:99440], is differentially expressed in 112 experiment(s);
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