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Transcriptomic analysis of the effect of ASO-mediated (40ug/day) CD33 knock-down on the microglial gene network in an APP/PS1 mouse model of Alzheimer’s disease. [LNA-013]

ABSTRACT: Microglia, the resident innate immune cells of the central nervous system (CNS), are increasingly recognized as critical for normal CNS function as well as for the pathophysiology of CNS disorders, including Alzheimer's disease (AD). Advances in transcriptomic analyses, such as weighted gene co-expression network analysis, reveal that the most perturbed gene networks identified in AD brains fall squarely within microglial pathways and these findings are consistent with genetic and epigenetic genome-wide association studies linking specific microglial genes to AD risk. Increased expression of full-length CD33 increases AD risk and CD33 is a component of the microglial gene network, yet relatively little is known about the significance of CD33 in this gene network or in microglial biology. To gain further insight into these questions, we first identified and characterized locked nucleic acid (LNA) antisense oligonucleotides (ASOs) as tools to knock down CD33 in APP/PS1 mice in vivo. We report here that CD33 LNA ASO results in robust knockdown of CD33 mRNA the frontal cortex and hippocampus of APP/PS1 mice and that this knockdown causes changes to the AD-associated microglial gene network. This work suggests that CD33 may be a viable therapeutic target in AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE74440 | GEO | 2016/09/30

SECONDARY ACCESSION(S): PRJNA300427

REPOSITORIES: GEO

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Transcriptomic analysis of the effect of ASO-mediated CD33 knock-down on the microglial gene network in an APP/PS1 mouse model of Alzheimer’s disease. [LNA-006]

Project description:Microglia, the resident innate immune cells of the central nervous system (CNS), are increasingly recognized as critical for normal CNS function as well as for the pathophysiology of CNS disorders, including Alzheimer's disease (AD). Advances in transcriptomic analyses, such as weighted gene co-expression network analysis, reveal that the most perturbed gene networks identified in AD brains fall squarely within microglial pathways and these findings are consistent with genetic and epigenetic genome-wide association studies linking specific microglial genes to AD risk. Increased expression of full-length CD33 increases AD risk and CD33 is a component of the microglial gene network, yet relatively little is known about the significance of CD33 in this gene network or in microglial biology. To gain further insight into these questions, we first identified and characterized locked nucleic acid (LNA) antisense oligonucleotides (ASOs) as tools to knock down CD33 in APP/PS1 mice in vivo. We report here that CD33 LNA ASO results in robust knockdown of CD33 mRNA the frontal cortex and hippocampus of APP/PS1 mice and that this knockdown causes changes to the AD-associated microglial gene network. This work suggests that CD33 may be a viable therapeutic target in AD.

2016-09-30 | GSE74437 | GEO

Transcriptomic analysis of the effect of ASO-mediated (50ug/day) CD33 knock-down on the microglial gene network in an APP/PS1 mouse model of Alzheimer’s disease. [LNA-012]

2016-09-30 | GSE74438 | GEO

Sex‐specific accelerated decay in time/activity‐dependent plasticity and associative memory in an animal model of Alzheimer's disease

Project description:In a series of slice electrophysiology experiments, we demonstrated that female APPSwe-Psen1dE9 Alzheimer's disease model mice show greater impairments in hippocampal synaptic plasticity than male mice of the same age and genotype. Female APP/PS1 mice also showed greater impairments in behavioural associative memory, higher amyloid plaque burden and increased microglial activation in the hippocampus than males at age 4-5 months. We thus profiled hippocampal mRNA from these mice to investigate the underlying molecular mechanisms. Compared to wild-type mice of the same sex, we found that female APP/PS1 mice showed a greater upregulation of microglial and inflammatory genes than males. Moreover, downregulation of genes associated with memory and plasticity was observed uniquely in female APP/PS1 mice. These data provide insight into the potential mechanisms of the greater prevalence and faster progression of AD in females.

2021-10-30 | GSE186710 | GEO

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

Characterization of the chromatin accessibility in an Alzheimer’s disease (AD) mouse model (ATAC-Seq)

Project description:The assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the AD-associated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA-sequencing.We identified 1690 increased AD-associated chromatin accessible regions in the hippocampal tissues of APP/PS1 mice and 1003 decreased chromatin accessible regions were considered to be related with declined AD-associated biological processes.In the APP/PS1 hippocampus, 1090 genes were found to be up-regulated and 1081 down-regulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting up-regulated mRNA levels.Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.

2020-07-09 | GSE145906 | GEO

Characterization of the chromatin accessibility in an Alzheimer’s disease (AD) mouse model (RNA-Seq)

2020-07-09 | GSE145907 | GEO

TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease

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

Age- and Nicotine-Associated Gene Expression Changes in the Hippocampus of APP/PS1 Mice

Project description:The etiology of Alzheimer's disease (AD) has been intensively studied. However, little is known about the molecular alterations in early-stage and late-stage AD. Hence, we performed RNA sequencing and assessed differentially expressed genes (DEGs) in the hippocampus of 18-month and 7-month-old APP/PS1 mice. Moreover, the DEGs induced by treatment with nicotine, the nicotinic acetylcholine receptor agonist that is known to improve cognition in AD, were also analyzed in old and young APP/PS1 mice. When comparing old APP/PS1 mice with their younger littermates, we found an upregulation in genes associated with calcium overload, immune response, cancer, and synaptic function; the transcripts of 14 calcium ion channel subtypes were significantly increased in aged mice. In contrast, the downregulated genes in aged mice were associated with ribosomal components, mitochondrial respiratory chain complex, and metabolism. Through comparison with DEGs in normal aging from previous reports, we found that changes in calcium channel genes remained one of the prominent features in aged APP/PS1 mice. Nicotine treatment also induced changes in gene expression. Indeed, nicotine augmented glycerolipid metabolism, but inhibited PI3K and MAPK signaling in young mice. In contrast, nicotine affected genes associated with cell senescence and death in old mice. Our study suggests a potential network connection between calcium overload and cellular signaling, in which additional nicotinic activation might not be beneficial in late-stage AD

2019-09-10 | GSE86828 | GEO

Total RNA Sequencing in microglia isolated from N-AS treated APP/PS1 mice

Project description:To examine the regulation of microglia by N-AS-triggered SPMs, we analyzed the gene expression patterns of microglia derived from WT, APP/PS1, and N-AS-injected APP/PS1 mice using RNAseq. These results indicated that N-AS-triggered SPMs activated an anti-inflammatory, positive immune response, and enhanced the phagocytic abilities of microglia in N-AS-treated APP/PS1 mice, leading to resolution of neuroinflammation and upregulation of phagocytic microglia in this AD animal model.

2020-02-29 | GSE146133 | GEO

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