Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA399530 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5956450.fastq.gz | Fastqsanger.gz | |||
| SRR5956460_1.fastq.gz | Fastqsanger.gz | |||
| SRR5956460_2.fastq.gz | Fastqsanger.gz | |||
| SRR5956470.fastq.gz | Fastqsanger.gz | |||
| SRR5956451.fastq.gz | Fastqsanger.gz |
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Project description:The impact of Apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cell models, post-mortem brain and APOE targeted replacement mice. Population and isogenic models uncover that APOE4 local haplotype rather than a single risk allele alone contributes to the risk. Global transcriptomic analyses reveal human specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 leads to elevated de novo cholesterol synthesis despite the intracellular cholesterol accumulation due to lysosomal sequestration of cholesterol in astrocytes. Transcriptome analyses uncovered Matrisome dysregulation associated with upregulated chemotaxis, glial activation and lipid biosynthesis in astrocytes, co-cultured with neurons that recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
2022-06-23 | GSE190187 | GEO
Project description:The impact of Apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cell models, post-mortem brain and APOE targeted replacement mice. Population and isogenic models uncover that APOE4 local haplotype rather than a single risk allele alone contributes to the risk. Global transcriptomic analyses reveal human specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 leads to elevated de novo cholesterol synthesis despite the intracellular cholesterol accumulation due to lysosomal sequestration of cholesterol in astrocytes. Transcriptome analyses uncovered Matrisome dysregulation associated with upregulated chemotaxis, glial activation and lipid biosynthesis in astrocytes, co-cultured with neurons that recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
2022-06-23 | GSE190186 | GEO
Project description:The impact of Apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cell models, post-mortem brain and APOE targeted replacement mice. Population and isogenic models uncover that APOE4 local haplotype rather than a single risk allele alone contributes to the risk. Global transcriptomic analyses reveal human specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 leads to elevated de novo cholesterol synthesis despite the intracellular cholesterol accumulation due to lysosomal sequestration of cholesterol in astrocytes. Transcriptome analyses uncovered Matrisome dysregulation associated with upregulated chemotaxis, glial activation and lipid biosynthesis in astrocytes, co-cultured with neurons that recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
2022-06-23 | GSE190185 | GEO
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
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
Project description:The apolipoprotein E (APOE) gene is the strongest genetic risk modifier for Alzheimer's disease (AD), with the APOE4 allele increasing risk and APOE2 decreasing it compared to the common APOE3 allele. Using single-nuclei RNA sequencing of the temporal cortex from APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, we found that AD-associated transcriptomic changes were highly APOE genotype-dependent. Comparing AD with controls, APOE2 carriers showed upregulated synaptic and myelination-related pathways, preserving synapses and myelination at the protein level. Conversely, these pathways were downregulated in APOE3 homozygotes, resulting in reduced synaptic and myelination proteins. In APOE4 carriers, excitatory neurons displayed reduced synaptic pathways similar to APOE3, but oligodendrocytes showed upregulated myelination pathways like APOE2. However, their synaptic and myelination protein levels remained unchanged or increased. APOE4 carriers also showed increased pro-inflammatory signatures in microglia but reduced responses to amyloid-β pathology. These findings reveal APOE genotype-specific molecular alterations in AD across cell types.
2025-03-17 | GSE237718 | GEO
Project description:In late-onset sporadic Alzheimer’s disease (AD), the most prevalent and strongest risk factor is the ε4 allele of the apolipoprotein E (APOE4). To investigate the pathophysiological effects of the APOE4 genotype in the human cellular context, we generated isogenic iPSC-derived astrocytes bearing APOE4 alleles from APOE3 control iPSC. Next, to identify astrocytic APOE4-specific secreted proteomes, we performed a mass spectrometry using culture media from human astrocytes carrying APOE3 or APOE4.
2023-09-01 | PXD044308 | JPOST Repository
Project description:Aging and its physiological manifestations have been correlated with adult stem cell exhaustion and a failure to maintain tissue homeostasis1-10. Since multiple morphological cellular defects are associated with aging-related disorders, we hypothesized that late onset disorders might be linked to adult stem cell abnormalities compromising cellular function over time. Our work shows that a dominant G2019S mutation in the human LRRK2 gene, which is associated with central nervous system disorders, including Parkinson’s disease, the second most prevalent neurodegenerative disease in the aging population, causes alterations in neural stem cell homeostasis in aging-related cellular contexts. They include disruption of the nuclear architecture, deficiencies in clonal expansion and alterations in neural differentiation assays as well as an increased susceptibility to proteasomal stress. These phenotypic changes are dependent on differential kinase activity manifested during cellular passaging. Our studies might open new venues for studying the influence of aging in neural stem cell dependent processes, such as cognitive impairments, in the degenerating diseased brain. Genome-wide localization of Histon K4 trimethylation in human iPSC and iPSC-derived neural stem cell using ChIP-seq
2013-01-01 | E-GEOD-34061 | biostudies-arrayexpress
Project description:Monomeric C-reactive protein (mCRP) plays a role in cerebrovascular damage mediated by apolipoprotein E4 (ApoE4) in Alzheimer's disease (AD) pathogenesis. Using proteomic profilings, we found altered cytoskeleton proteins in the microvasculature of AD brains, including increased levels of hyperphosphorylated tau (pTau) and the actin-related protein, LIMA1. To address the hypothesis that cytoskeletal changes serve as early pathological signatures in brain endothelia for AD, ApoE4 knock-in mice intraperitoneal injected with mCRP revealed that mCRP bound to CD31 to increase LIMA1 expression and facilitate the binding of phosphorylated CD31 (pCD31) to LIMA1. mCRP combined with APOE4 protein altered the expression of various actin cytoskeleton proteins along with decreased interaction of CD31 and VE-Cadherin, causing microvasculature damage. Notably, the APOE2 protein attenuated these changes. Overall, the ApoE4-mCRP-CD31 pathway acts via pCD31-LIMA1 interaction to disrupt the adherens junctions and the actin cytoskeleton, leading to endothelial barrier dysfunction in the brain and increased AD risk.
2025-05-06 | PXD051529 | Pride
Project description:iPSC-derived brain organoids with microglial cells (assembloids) were used for this study. We used single cell RNA sequencing (scRNA-seq) to analyze the difference between APOE3 and APOE4 genotypes
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