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PSEN1ΔE9, APPswe and APOE4 confer disparate phenotypes in human iPSC-derived microglia

ABSTRACT: PSEN1ΔE9, APPswe and APOE4 confer disparate phenotypes in human iPSC-derived microglia

PROVIDER: PRJNA559812 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9951050.fastq.gz	Fastqsanger.gz
	SRR9951051.fastq.gz	Fastqsanger.gz
	SRR9951052.fastq.gz	Fastqsanger.gz
	SRR9951053.fastq.gz	Fastqsanger.gz
	SRR9951054.fastq.gz	Fastqsanger.gz

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PSEN1ΔE9, APPswe and APOE4 confer disparate phenotypes in human iPSC-derived microglia

Project description:Here we elucidate the effect of Alzheimer’s disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9 and APPswe, on functionality of human microglia. We present a physiologically relevant high-yield protocol for producing human microglia-like cells (iMGLs) from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to recreate microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.

2019-10-08 | GSE135707 | GEO

PSEN1?E9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia.

Project description:Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1?E9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1?E9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.

| S-EPMC6829767 | biostudies-literature

Differential gene expression in APOE3 and APOE4 gene targeted replacement mice

Project description:The aim of the study was to investigate hepatic gene expression profiles differentially regulated by the APOE genotype in gene targeted replacement mice. The APOE4 genotype is associated with increased mortality in the elderly and is an independent risk factor for age-dependent chronic diseases. However, little is known about the underlying mechanisms and molecular targets involved in the APOE4-risk association. As APOE is centrally involved in lipid and cholesterol metabolism and in large part is produced in the liver, we analyzed hepatic RNA profiles of APOE4- and APOE3-expressing mice. 2 groups of 5 animals with 1 liver extract per animal. Mice were homozygous for a human APOE3 or APOE4 gene targeted replacement of the endogenous mouse Apoe gene (B6.129P2-Apoetm2(APOE*3)Mae N8 or B6.129P2-Apoetm3(APOE*4)Mae N8, Taconic Transgenic ModelsM-bM-^DM-", http://www.taconic.com/wmspage.cfm?parm1=2542), purchased at the age of 6-8 weeks, strain C57BL/6, 3 months old at the performance of the microarray, 6 weeks on a high-fat diet containing 41% energy from milk fat and 2 g/kg cholesterol.

2012-12-15 | E-GEOD-42930 | biostudies-arrayexpress

MicroRNA expression data from APPswe/PS1deltaE9 transgenic mice cortex

Project description:To characterize the differentially expressed microRNAs between APPswe/PS1deltaE9 transgenic mice cortex and normal wild type mice cortex We isolated APPswe/PS1delataE9 and wild type mice brain cortexes for microRNA sequencing.

2015-03-05 | E-GEOD-55589 | biostudies-arrayexpress

Two pathogenic germline truncating variants of BRCA2 confer different haploinsufficiency phenotypes

Project description:Two pathogenic germline truncating variants of BRCA2 confer different haploinsufficiency phenotypes

| PRJNA1136477 | ENA

APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types

Project description:The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Ab42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Ab uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Ab phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant.

2018-05-31 | GSE102956 | GEO

MicroRNA expression data from APPswe/PS1deltaE9 transgenic mice cortex

Project description:To characterize the differentially expressed microRNAs between APPswe/PS1deltaE9 transgenic mice cortex and normal wild type mice cortex

2015-03-05 | GSE55589 | GEO

Comparaison of APOE4 and APOE3 transcriptomic profiles from derived cell lines in absence or presence of an inflammatory stimulus

Project description:Our objective was to study some of the molecular changes that associate with APOE4, ultimately aiming at identifying new mechanisms that support exacerbated neuroinflammation as a cause of functional deterioration in Alzheimer's disease (AD). We hypothesize that the increased risk of developing AD in APOE4 carriers could be the consequence of altered inflammatory regulatory functions in astrocytes, which would be key effectors of the pathological process.

2021-02-01 | E-MTAB-9625 | biostudies-arrayexpress

APOE4-dependent transcriptome changes in human iPSC-derived astrocytes

Project description:APOE4 genotype is the strongest risk factor for the pathogenesis of sporadic Alzheimer’s disease (AD), but the detailed molecular mechanism of APOE4-mediated synaptic impairment remains to be determined in human cellular context. In this study, we generated human astrocyte model carrying APOE3 or APOE4 genotype using human induced pluripotent stem cells (iPSCs), in which isogenic APOE4 iPSCs were genome-edited from healthy control APOE3 iPSCs. By transcriptome analysis of human astrocytes between APOE genotypes, we showed the upregulation of an extracellular matrix glycoprotein in human APOE4 astrocytes, which may cause synaptic degeneration in concert with the equivocal reactive character and lipid change. Together, these results demonstrate novel negative impact of human APOE4 astrocyte on synaptic integrity and lead to a promising therapeutic intervention into APOE4-carriers.

2023-08-31 | GSE206314 | GEO

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

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