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Fragmentation of apolipoprotein E4 is required for differential expression of inflammation and activation related genes in microglia cells

ABSTRACT: Fragmentation of apolipoprotein E4 is required for differential expression of inflammation and activation related genes in microglia cells

PROVIDER: PRJNA725279 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14328310.fastq.gz	Fastqsanger.gz
	SRR14328311.fastq.gz	Fastqsanger.gz
	SRR14328312.fastq.gz	Fastqsanger.gz
	SRR14328313.fastq.gz	Fastqsanger.gz
	SRR14328314.fastq.gz	Fastqsanger.gz

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Fragmentation of apolipoprotein E4 is required for differential expression of inflammation and activation related genes in microglia cells

Project description:This study assessed the effects of the full-length ApoE4 protein on modulating the transcriptome of BV2 microglial cells and comparing to a previous report looking at an amino-terminal fragment of ApoE4 (residues 1-151). The results indicated that full-length ApoE4 had a very small effect on gene expression compared to the fragment. Only 48 differentially expressed genes (DEGs) were identified (p<0.05, and greater than 2-fold change). A gene ontology analysis of these DEGs indicated that they are not involved in inflammatory and activation processes, in contrast to the genes upregulated by the E4-fragment. In addition, genes that showed a negative fold-change upon FL-E4 treatment typically showed a strong positive fold-change upon treatment with the fragment (Pearson’s r=-0.7). Taken together, these results support the hypothesis that a key step in the conversion of microglia to an activated phenotype is proteolytic cleavage of FL-ApoE4. Therefore, the neutralization of this amino-terminal fragment of ApoE4, specifically, may serve as an important therapeutic strategy in the treatment of AD.

2021-04-27 | GSE173381 | GEO

Peripheral immunomodulatory effects of Apolipoprotein E4 on Alzheimer's disease - Immune Enrichment

Project description:Apolipoprotein E (APOE) is a lipid and cholesterol transport molecule known to influence Alzheimer's disease (AD) risk in an isoform-specific manner. In particular, the APOE E4 allele is the largest genetic risk factor for late-onset sporadic AD. Our recent findings uncovered activated, clonally expanded T cells in AD cerebrospinal fluid (CSF). This T cell phenotype occurred concomitantly with altered expression of APOE in CSF monocytes. Yet, whether APOE variants differentially affect peripheral immunity systems remains unknown. In this study, we performed targeted immune profiling using single-cell epigenetic and transcriptomic analysis of peripheral blood mononuclear cells (PBMC). We analyzed 55 age-matched healthy control (HC) and AD patients with equal distribution of APOE E3/E3, E3/E4, and E4/E4 genotypes. We reveal dysregulation in monocytes and clonally expanded T cells that are distinct to AD patients carrying the APOE E4/E4 genotype. Additionally, we find APOE isoform-dependent chromatin accessibility differences that correspond to RNA expression changes. Cumulatively, these results uncover APOE isoform-dependent changes to peripheral immunity in AD.

2024-03-22 | GSE227991 | GEO

In Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons

Project description:Despite its clear impact on Alzheimer’s Disease (AD) risk, apolipoprotein (apo) E4’s contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplanted human induced pluripotent stem cell (hiPSC)-derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knock-in mouse hippocampi, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment. Using single nucleus RNA-sequencing (snRNA-seq), we identified key transcriptional changes specific to human neuron subtypes in response to endogenous or exogenous apoE4. We also found that Aβ from transplanted human neurons formed plaque-like aggregates, with differences in localization and interaction with microglia depending on the transplant and host apoE genotype. These findings highlight the power of in vivo chimeric disease modeling for studying AD.

2020-06-20 | GSE152867 | GEO

Reduced binding of apolipoprotein E4 isoform to complement factor H promotes amyloid-beta induced neuroinflammation

Project description:Brain total lysate from ad patient. Reduced binding of apolipoprotein E4 isoform to complement factor H promotes amyloid-beta induced neuroinflammation.

2021-12-27 | MSV000088618 | MassIVE

Peripheral immunomodulatory effects of Apolipoprotein E4 on Alzheimer's disease - Immune Enrichment

Project description:Peripheral immunomodulatory effects of Apolipoprotein E4 on Alzheimer's disease - Immune Enrichment

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In Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons

Project description:In Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons

| PRJNA640668 | ENA

Phospholipid composition of APOE lipoproteins affects microglia activation in an isoform-specific manner

Project description:Apolipoprotein E4 (APOE) is the strongest genetic risk factor for Alzheimer's disease (AD). Our lipidomic analysis identified a common phospholipid signature with a high level of correlation between APOEε3/3 and APOEε4/4 AD postmortem brain samples and native lipoproteins isolated from astrocyte conditioned media of mice expressing human APOE3 or APOE4. Behavioral testing demonstrated that native E3 lipoproteins were more effective than E4 at ameliorating the harmful effects of Aβ on cognition. We posit that APOE isoform-specific differences in the phospholipid composition of native lipoproteins prompt a differential microglial response. Using time-lapse in vivo two-photon imaging, we compared the effect of E3 or E4 infused with Aβ and determined that E3 lipoproteins induced a faster microglial migration towards Aβ. To determine how E3 and E4 lipoproteins affect microglial transcriptome in response to Aβ, we performed bulk and single cell RNA-seq of WT and Trem2ko mice. We show that compared to E4, cortical infusion of E3 lipoproteins upregulated a higher proportion of genes associated with an activated immune response accompanied by a downregulation of homeostatic genes. scRNA-seq identified microglia-specific clusters affected by Trem2 deficiency, suggesting that lack of Trem2 impairs the transition of microglia from homeostatic to an activated state. Compared to E3, E4-expressing microglia showed a reduced Aβ uptake that was additionally aggravated by Trem2 deficiency. Together, our findings have elucidated unique phenotypic and transcriptional differences in the microglial response to Aβ in the presence of E3 or E4 lipoproteins which could impact AD pathogenesis.

2021-04-30 | GSE158962 | GEO

APOE4 genotype confers transcriptomic and functional alterations to primary mouse microglia

Project description:Relative to E3 microglia, E4 microglia exhibit altered morphology, increased numbers of endosomes and lysosomes, increased cytokine/chemokine production, and increased lipid accumulation at baseline. These changes were accompanied by increased activation of kinases that mediate global repression of translation. In a subsequent phagocytosis assay, E4 microglia exhibited increased accumulation of a variety of substrates when compared to E3 microglia. While transcriptomic profiling of myelin-challenged microglia revealed a largely overlapping response profile across genotypes, differential regulation of several pathways including interferon-related signaling, translation-related processes was identified in E4 versus E3 microglia both at baseline and following myelin challenge. Here we identify and describe several important functional alterations in E4 relative to E3 microglia. Together, our results suggest E4 genotype confers elevated levels of baseline stress to microglia relative to E3 genotype, even prior to treatment with exogenous stimuli. This work provides insight into the molecular mechanisms by which E4 genotype may increase risk for AD.

2022-03-17 | GSE171280 | GEO

Alcanivorax sp. E4 strain:E4

Project description:Alcanivorax sp. E4 strain:E4 Genome sequencing

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APOE4 retinal microglia remain homeostatic in glaucoma.

Project description:The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer’s disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here we find that in two mouse glaucoma models and in human glaucomatous retinas, microglia transition to a neurodegenerative (MGnD) phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3). Mice in which Apoe was targeted in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss despite elevated intraocular pressure (IOP). Similar to Apoe–/– retinal microglia, APOE4 microglia did not upregulate MGnD genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma, and that the APOE-Galectin-3 signaling pathway can be targeted to treat this blinding disease.

2022-08-16 | GSE192507 | GEO