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The CD33 short isoform is a gain-of-function variant that enhances Aß1-42 phagocytosis in microglia

ABSTRACT: The CD33 short isoform is a gain-of-function variant that enhances Aß1-42 phagocytosis in microglia

PROVIDER: PRJNA723594 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14295970.fastq.gz	Fastqsanger.gz
	SRR14295971.fastq.gz	Fastqsanger.gz
	SRR14295972.fastq.gz	Fastqsanger.gz
	SRR14295973.fastq.gz	Fastqsanger.gz
	SRR14295974.fastq.gz	Fastqsanger.gz

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The CD33 short isoform is a gain-of-function variant that enhances Aß1-42 phagocytosis in microglia II

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

The CD33 short isoform is a gain-of-function variant that enhances Aß1-42 phagocytosis in microglia I

2021-04-21 | GSE172525 | GEO

The CD33 short isoform is a gain-of-function variant that enhances Aß1-42 phagocytosis in microglia I

Project description:The CD33 short isoform is a gain-of-function variant that enhances Aß1-42 phagocytosis in microglia I

| PRJNA723598 | ENA

The CD33 short isoform is a gain-of-function variant that enhances Aß1-42 phagocytosis in microglia II

Project description:The CD33 short isoform is a gain-of-function variant that enhances Aß1-42 phagocytosis in microglia II

| PRJNA723599 | ENA

The CD33 short isoform is a gain-of-function variant that enhances Aß1-42 phagocytosis in microglia

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-04-21 | GSE172528 | GEO

The CD33 short isoform is a gain-of-function variant that enhances Aβ<sub>1-42</sub> phagocytosis in microglia.

Project description:BackgroundCD33 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.MethodsWe 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.ResultsIn 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.ConclusionsThese 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.

| S-EPMC7992807 | biostudies-literature

Deletion of the Alzheimer’s Disease-associated CD33 results in increased phagocytosis, oxidative burst and inflammation

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

Genome-wide expression profile on hiPSCs and hiPSC-derived CD33+ myeloid cells

Project description:To gain insights into which pathways might be dysregulated in JMML, we compared the transcriptome profiles among hiPSC and sorted CD33+ myeloid cells from control and patient samples. NS/JMML-derived CD33+ myeloid cells showed dysregulation in major biological processes. Moreover, a consistent expression pattern among sets of genes related to pluripotency and myeloid regulation was observed in the control, NS and NS/JMML CD33+ myeloid cells further supporting generally successful myelopoiesis. Total RNA obtained from hiPSC and sorted CD33+ myeloid cells (at day 14 of differentiation) from control and patient samples

2014-01-31 | E-GEOD-54538 | biostudies-arrayexpress

Genome-wide expression profile on hiPSCs and hiPSC-derived CD33+ myeloid cells

2014-01-31 | GSE54538 | GEO

Deletion of the Alzheimer’s Disease-associated CD33 results in increased phagocytosis, oxidative burst and inflammation

Project description:Deletion of the Alzheimer’s Disease-associated CD33 results in increased phagocytosis, oxidative burst and inflammation

| PRJNA650315 | ENA