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APOE determines cell type-specific pathological landscape of Alzheimer's disease

ABSTRACT: APOE determines cell type-specific pathological landscape of Alzheimer's disease

PROVIDER: PRJNA996223 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25336100.fastq.gz	Fastqsanger.gz
	SRR25336200.fastq.gz	Fastqsanger.gz
	SRR25336101.fastq.gz	Fastqsanger.gz
	SRR25336201.fastq.gz	Fastqsanger.gz
	SRR25336102.fastq.gz	Fastqsanger.gz

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APOE determines cell type-specific pathological landscape of Alzheimer's disease

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

ApoE determines the metabolic fate of apoC-III

Project description:Hypertriglyceridemia results from accumulation of triglyceride (TG)-rich lipoproteins (TRLs) in the circulation and is associated with increased cardiovascular disease risk. ApoC-III is an apolipoprotein on TRLs and a prominent negative regulator of TG catabolism. We recently established that in vivo apoC-III predominantly inhibits LDLR and LRP1 mediated hepatic TRL clearance and that apoC-III enriched TRLs are preferentially cleared by syndecan-1 (SDC1). In this study, we determined the impact of apoE, a common ligand for all three receptors, on apoC-III metabolism using apoC-III antisense oligonucleotide (ASO) treatment in mice lacking apoE and functional SDC1 (Apoe(-/-) Ndst1(f/f) Alb-Cre+). ApoC-III ASO treatment significantly reduced plasma TG levels in Apoe(-/-) Ndst1(f/f) Alb-Cre+ mice without reducing hepatic VLDL production or improving hepatic TRL clearance. Further analysis revealed that apoC-III ASO treatment lowered plasma TGs in Apoe(-/-) Ndst1(f/f) Alb-Cre+ mice, which was associated with increased LPL activity in white adipose tissue (WAT) in the fed state. Finally, clinical data confirm that ASO-mediated lowering of apoC-III via volanesorsen can reduce plasma TG levels independent of the apoE isoform genotype. Our data indicate that apoE determines the metabolic impact of apoC-III as we establish that apoE is essential to mediate inhibition of TRL clearance by apoC-III and that in the absence of functional apoE apoC-III inhibits tissue LPL activity.

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ApoE determines the metabolic fate of apoC-III

Project description:ApoE determines the metabolic fate of apoC-III

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scRNAseq and scATACseq of Cd45+ cells from brains of 5XFAD mice bearing distinct APOE alleles and across age

Project description:Here we analyze the gene expression and chromatin accessibility landscape of immune cells in the brains of 5XFAD mice, a common model of Alzheimer's disease, bearing knock-in of human APOE variants in the mouse APOE locus, and aged to 10, 20, 60, or 96 weeks of age.

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Molecular landscape of immature neurons in the human hippocampus in Alzheimer's disease

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Microglial-expressed Apoe does not modulate plaque pathogenesis

Project description:This dataset allows for the exploration of the effect of microglial-expressed Apoe knockout in a 5xFAD Alzheimer's Disease model.

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Microarray analysis of the astrocyte transcriptome in the ageing brain: relationship to Alzheimer's pathology and ApoE genotype

Project description:Astrocyte dysfunction impacts their normal function, including neuronal support, thereby contributing to neurodegenerative pathologies including Alzheimer's disease (AD). Therefore to understand the role of astrocytes in the pathogenesis of age-related disorders we analysed the gene expression profile of astrocytes with respect to Alzheimer-type pathology. The aim of the present study was to combine immuno-LCM and microarray analysis to characterise the astrocyte transcriptome at different Braak stages, and with respect to ApoE genotype, in post-mortem human temporal cortex sampled dervied from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS). GFAP-positive astrocytes were isolated from age, sex and brain pH-matched cases derived from the MRC-CFAS cohort, using immuno laser capture microdissection. The extracted RNA was amplified and applied to HGU133 Plus 2.0 Affymetrix gene arrays. Genes were considered differentially expressed if they showed a minimum 1.5 fold change at p<0.02 in all 6 individual cases in each stage of pathology [18 cases in total: 6 cases Braak stages I-II (3 cases carried at least one ApoE epsilon4 allele and 3 were ApoEe4 negative); 6 cases Braak stages III-IV (3 ApoEe4 positive and 3 ApoEe4 negative; 6 cases Braak stages V-VI (3 ApoEe4 positive and 3 ApoEe4 negative)]. keywords: human GFAP-positive astrocytes

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Microarray analysis of the astrocyte transcriptome in the ageing brain: relationship to Alzheimer's pathology and ApoE genotype

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APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia

Project description:The major genetic risk factor for Alzheimer’s disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.

2024-10-04 | GSE252454 | GEO

scRNAseq of Cd45+ cells from brains of Aducanumab-treated ApoE-variant Alzheimer's mice

Project description:scRNAseq of Cd45+ cells from brains of Aducanumab-treated ApoE-variant Alzheimer's mice

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