Early amyloid-induced changes in microglia gene expression in APP/PS1 mice
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ABSTRACT:
PROVIDER: PRJNA942284 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23750700_1.fastq.gz | Fastqsanger.gz | |||
| SRR23750700_2.fastq.gz | Fastqsanger.gz | |||
| SRR23750701_1.fastq.gz | Fastqsanger.gz | |||
| SRR23750701_2.fastq.gz | Fastqsanger.gz | |||
| SRR23750702_1.fastq.gz | Fastqsanger.gz |
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Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from APPswe/PS1dE9 (APP/PS1) mice and wildtype littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentally reflect the initial response of microglia to Aβ.
2024-04-01 | GSE226938 | GEO
Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from APPswe/PS1dE9 (APP/PS1) mice and wildtype littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentally reflect the initial response of microglia to Aβ.
2024-04-01 | GSE226937 | GEO
Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.
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Project description:Early amyloid-induced changes in microglia gene expression in APP/PS1 mice [scRNA-seq]
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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
Project description:Early amyloid-induced changes in microglia gene expression in APP/PS1 mice [bulk RNA-seq]
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Project description:RNA samples from the cerebral cortex of APP/PS1 and WT mouse littermates aged 3, 6 and 12 months were analyzed using the Affymetrix Genechip Mouse Gene 1.1 ST Array. The APP-PS1 transgenic mouse express the human mutated forms APPswe and PS1dE9. This is a good model of familial Alzheimer Disease because it reproduces several features of the disease as β-amyloid deposits throughout the brain and exhibit memory impairment by the end of the sixth month and is a simple model to study the molecular pathways. The aim of this study is to identify dysregulation of inflammation pathways in order to understand shifts of inflammation responses with disease progression.
2014-04-30 | E-MTAB-2121 | biostudies-arrayexpress
Project description:Aβ is a peptide of 39-42 amino acid residues that derived from putative intramembranous processing of amyloid precursor protein (APP) at the proposed active site of the γ-secretase/PS1 aspartyl. Aβ has been shown to aggregate and accumulate abnormally in the brain of AD (Alzheimer's disease), and extracellular amyloid plaques of Aβ peptides aggregation can trigger a cascade of pathologic events leading to nerve fiber entanglement and neuronal apoptosis protease. We used microarrays to investigate the effects of HPYD on the gene expression of APP/PS1 transgenic mice, the brain tissues of control group, model group and HPYD group mice.
2018-02-23 | GSE104249 | GEO
Project description:Two microglial TAM receptor tyrosine kinases - Axl and Mer - have been linked to Alzheimer’s disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer’s disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia is coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer’s disease, sIngle cell RNAseq analysis comparing wild type microglia with those with Axl and Mer deficiency reveals a similar disease state transitional program of microglia but a dampened differential expression of numerous AD siganture genes in microglia lacking TAM receptors. In line with the transcriptomic data, using two-photon microscopy, we show that genetic ablation of Axl and Mer results in microglia that are unable to normally detect, respond to, organize, or phagocytose amyloid beta plaques. These major deficits notwithstanding, and contrary to expectation, TAM-deficient APP/PS1 mice develop fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques, and that TAM-driven microglial phagocytosis does not constrain, but rather promotes, plaque development.
2021-02-25 | GSE160523 | GEO
Project description:The gut microbiota and innate immune system play critical roles in Alzheimer’s disease (AD). Bacteroides is elevated in AD patients and correlates with cerebrospinal fluid levels of Aβ and tau. We found that increased amyloid-β (Aβ) plaques in Bacteroides fragilis treated APP/PS1-21 mice were associated with altered cortical expression Aβ processing genes. B. fragilis suppressed peripheral CD4+ T cell production of GM-CSF and IL-4 and transcriptional changes in microglia related to GM-CSF and IL-4 signaling, phagocytosis, and protein degradation. Furthermore, B. fragilis impaired the microglial uptake of intracranially injected Aβ42, whereas Erysipelotrichaceae strains increased uptake. Depleting murine Bacteroidetes with metronidazole decreased amyloid load in aged 5xFAD mice, increased CD4+ T cell GM-CSF production, and activated microglial pathways related to cytokine signaling, phagocytosis and lysosomal degradation. These data suggest that the gut microbiome may contribute to AD pathogenesis by suppressing peripheral cytokines and microglia phagocytic function, leading to impaired immune-mediated Aβ clearance.
2024-10-12 | GSE215438 | GEO