Phospholipid composition of APOE lipoproteins affects microglia activation in an isoform-specific manner
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA667096 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12766300.fastq.gz | Fastqsanger.gz | |||
| SRR12766301.fastq.gz | Fastqsanger.gz | |||
| SRR12766302.fastq.gz | Fastqsanger.gz | |||
| SRR12766303.fastq.gz | Fastqsanger.gz | |||
| SRR12766304.fastq.gz | Fastqsanger.gz |
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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.
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Project description:This SuperSeries is composed of the following subset Series: GSE25108: MicroRNAs are Transported in Plasma and Delivered to Recipient Cells by High-Density Lipoproteins (Human HDL miRNA Signatures) GSE25110: MicroRNAs are Transported in Plasma and Delivered to Recipient Cells by High-Density Lipoproteins (Human HDL and Exosome miRNA Signatures) GSE25149: MicroRNAs are Transported in Plasma and Delivered to Recipient Cells by High-Density Lipoproteins (Human exosome, LDL, and HDL miRNA Signatures) GSE25150: MicroRNAs are Transported in Plasma and Delivered to Recipient Cells by High-Density Lipoproteins (Mouse HDL signatures from WT and LDLR-/- high fat diet) GSE25311: MicroRNAs are Transported in Plasma and Delivered to Recipient Cells by High-Density Lipoproteins (HG-U133 2.0) GSE25424: MicroRNAs are Transported in Plasma and Delivered to Recipient Cells by High-Density Lipoproteins (microRNA signatures retrieved from rHDL injected into WT, ApoE-/- chow, ApoE-/-high fat diet) Refer to individual Series
2011-04-03 | E-GEOD-25425 | biostudies-arrayexpress
Project description:Apolipoprotein E (ApoE) polymorphisms modify the risk of neurodegenerative disease. To elucidate how ApoE isoforms alter the proteome, we applied in vivo deuterium isotope labeling to transgenic mice modified to express the human ApoE gene (isoform 2, 3, or 4). We employed liquid-chromatography and mass-spectrometry which allowed us to simultaneously measure relative protein concentration and track the incorporation of heavy isotopes over a 32-day period. The conjunction of turnover data with concentration measurements provides insight as to how ApoE isoforms affect the synthesis and degradation of a wide variety of proteins. We tested the homeostatic regulation of >2700 ontologies and quantified significant isoform-dependent changes which link ApoE genotype to modulation of mitochondrial components, oxidative phosphorylation, and maintenance of protein quality. Here we demonstrate the application of turnover rate measurement to further characterize concentration changes and provide opportunities for further exploration into disease pathology. (Zuniga 2023)
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Project description:APOE and Trem2 are major genetic risk factors for Alzheimer's disease (AD), but how they affect microglia response to Aβ remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brain and lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using preclinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aβ, facilitate Aβ uptake, and ameliorate Aβ effects on cognition. Bulk and single-cell RNA-seq demonstrate that, compared to APOE4, cortical infusion of APOE3 lipoproteins upregulates a higher proportion of genes linked to an activated microglia response, and this trend is augmented by TREM2 deficiency. In vitro, lack of TREM2 decreases Aβ uptake by APOE4-treated microglia only, suggesting TREM2-APOE interaction. Our study elucidates phenotypic and transcriptional differences in microglial response to Aβ mediated by APOE3 or APOE4 lipoproteins in preclinical models of AD.
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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.
2019-05-24 | GSE131284 | GEO
Project description:APOE is the main genetic modifier for late onset Alzheimer’s disease (LOAD). While an APOE2/APOE3/APOE4 allelic series is well established for LOAD risk and neuropathology, molecular mechanisms underlying isoform-dependent risk and relevance of ApoE-associated lipids remain elusive. Here, we studied the effects of LPS stimulation on APOE KO iPSC-derived microglia treated with different ApoE isoforms (ApoE2/E3/E4) pre-complexed with BODIPY-cholesteryl ester (CE) and HDL -/+ recombinant LDLR extracellular domain.
2024-11-10 | GSE250249 | GEO
Project description:Human apolipoprotein E (apoE) exists in three isoforms: apoE2, apoE3 and apoE4. APOE ε4 is a major genetic risk factor for cardiovascular disease (CVD) and Alzheimer's disease (AD). ApoE mediates cholesterol metabolism by binding various receptors. The low-density lipoprotein receptor (LDLR) has a high affinity for apoE, and is the only member of its receptor family to demonstrate an apoE isoform specific binding affinity (E4>E3>>E2). Evidence suggests that a functional interaction between apoE and LDLR influences the risk of CVD and AD. We hypothesize that the differential cognitive effects of the apoE isoforms are a direct result of their varying interactions with LDLR. To test this hypothesis, we have employed transgenic mice that express human apoE2, apoE3, or apoE4, and either human LDLR (hLDLR) or no LDLR (LDLR(-/-)). Our results show that plasma and brain apoE levels, cortical cholesterol, and spatial memory are all regulated by isoform-dependent interactions between apoE and LDLR. Conversely, both anxiety-like behavior and cued associative memory are strongly influenced by APOE genotype, but these processes appear to occur via an LDLR-independent mechanism. Both the lack of LDLR and the interaction between E4 and the LDLR were associated with significant impairments in the retention of long term spatial memory. Finally, levels of hippocampal apoE correlate with long term spatial memory retention in mice with human LDLR. In summary, we demonstrate that the apoE-LDLR interaction affects regional brain apoE levels, brain cholesterol, and cognitive function in an apoE isoform-dependent manner.
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Project description:Circulating microRNAs (miRNA) are relatively stable in plasma and are a new class of disease biomarkers. Here we present evidence that human high-density lipoprotein (HDL) transports endogenous miRNAs and delivers them to recipient cells with functional targeting capabilities. Highly-purified fractions of human HDL contain small RNAs, and the HDL-miRNA profile from normal subjects is significantly different than familial hypercholesterolemia subjects. miRNAs were demonstrated to associate with both native and reconstituted HDL particles, and reconstituted HDL injected into mice retrieved distinct miRNA profiles from normal and atherogenic models. Cellular export of miRNAs to HDL was demonstrated to be regulated by neutral sphingomyelinase. HDL-mediated delivery of miRNAs to recipient cells was demonstrated to be scavenger receptor BI-dependent. Furthermore, HDL delivery of both exogenous and endogenous miRNAs resulted in the direct targeting of mRNA reporters. Notably, HDL-miRNA from atherosclerotic subjects induced differential gene expression, with significant loss of conserved mRNA targets in cultured hepatocytes. Collectively, these observations suggest that HDL participates in a novel mechanism of intercellular communication involving the transport and delivery of miRNAs. microRNA signatures retrieved from rHDL injected into WT, ApoE-/- chow, ApoE-/-high fat diet Profiled rHDL miRNA signatures from n=3 WT; n=3 ApoE-/- chow, n=4 ApoE-/- high fat mice
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