Cell-type-specific regulation of APOE and CLU levels in human neurons by the Alzheimer’s disease risk gene SORL1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA997371 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25388463_1.fastq.gz | Fastqsanger.gz | |||
| SRR25388463_2.fastq.gz | Fastqsanger.gz | |||
| SRR25388464_1.fastq.gz | Fastqsanger.gz | |||
| SRR25388464_2.fastq.gz | Fastqsanger.gz | |||
| SRR25388465_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 72 |
Similar Datasets
Project description:SORL1 is implicated in the pathogenesis of Alzheimer’s disease (AD) through genetic studies. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs are differentiated to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 leads to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. SORL1 loss induces a neuron-specific reduction in APOE and CLU and altered lipid profiles. Enhancement of retromer-mediated trafficking rescues tau phenotypes observed in SORL1 null neurons but does not rescue APOE levels. Pathway analyses implicate TGF-β/SMAD signaling in SORL1 function, and modulating SMAD signaling in neurons alters APOE RNA levels in a SORL1-dependent manner. Analyses of iPSCs derived from a large cohort reveal a neuron-specific association between SORL1, APOE, and CLU levels, a finding validated in post-mortem brain. These studies provide a mechanistic link between strong genetic risk factors for AD.
2023-10-24 | PXD044093 | Pride
Project description:SORL1 is strongly implicated in the pathogenesis of Alzheimer’s disease (AD) through human genetic studies that point to an association of reduced SORL1 levels with higher risk for AD. To interrogate the role(s) of SORL1 in human brain cells, SORL1 null iPSCs were generated, followed by differentiation to neuron, astrocyte, microglial, and endothelial cell fates. Loss of SORL1 led to alterations in both overlapping and distinct pathways across cell types, with the greatest effects in neurons and astrocytes. Intriguingly, SORL1 loss led to a dramatic neuron-specific reduction in APOE and CLU levels, an increase in the accumulation of lipid droplets and altered lipid profiles. Pathway analysis implicated intracellular transport pathways and TGF-β/SMAD signaling in the function of SORL1 in neurons. Enhancement of retromer-mediated trafficking and autophagy rescued tau phenotypes observed in SORL1 null neurons but did not rescue APOE levels. However, stimulation and inhibition of SMAD signaling in neurons modulated APOE RNA levels in a SORL1-dependent manner. Further, analyses of iPSCs derived from a human aging cohort revealed a neuron-specific linear correlation between SORL1 and APOE RNA and protein levels, a finding validated in human post-mortem brain. These studies provide a mechanistic link between two of the strongest genetic risk factors for AD.
2023-07-24 | GSE238013 | GEO
Project description:Genetic studies implicate Clusterin (CLU) in the pathogenesis of Alzheimer’s disease (AD), yet its precise molecular impact remains unclear. Through unbiased proteomic profiling and functional validation in CLU-deficient astrocytes, we identify increased NfkB-dependent signaling and complement C3 secretion. Reduction of astrocyte CLU induced microglia dependent modulation of extracellular APOE and phosphorylated tau, as well as increased microglial phagocytosis and reduced synapse numbers. By integrating mouse and human cellular models with comprehensive analyses of human plasma and brain tissue, we demonstrate that CLU AD risk alleles are associated with reduced CLU protein and heightened inflammatory profiles. These findings establish a mechanistic link between AD genetic risk factors, astrocyte reactivity, and microglia-mediated effects on synaptic integrity. Collectively, these results support a model in which CLU upregulation in response to neuropathology is associated with maintenance of cognitive function, while diminished astrocyte CLU levels heighten disease susceptibility.
2025-04-28 | GSE294133 | GEO
Project description:Genetic studies implicate Clusterin (CLU) in the pathogenesis of Alzheimer’s disease (AD), yet its precise molecular impact remains unclear. Through unbiased proteomic profiling and functional validation in CLU-deficient astrocytes, we identify increased NfkB-dependent signaling and complement C3 secretion. Reduction of astrocyte CLU induced microglia dependent modulation of extracellular APOE and phosphorylated tau, as well as increased microglial phagocytosis and reduced synapse numbers. By integrating mouse and human cellular models with comprehensive analyses of human plasma and brain tissue, we demonstrate that CLU AD risk alleles are associated with reduced CLU protein and heightened inflammatory profiles. These findings establish a mechanistic link between AD genetic risk factors, astrocyte reactivity, and microglia-mediated effects on synaptic integrity. Collectively, these results support a model in which CLU upregulation in response to neuropathology is associated with maintenance of cognitive function, while diminished astrocyte CLU levels heighten disease susceptibility.
2025-04-28 | GSE289565 | GEO
Project description:Disease causal mechanism remains largely unknown for most Alzheimer’s disease (AD) genome-wide association studies (GWAS) risk loci, including the Clusterin (CLU) locus. Here, leveraging our approach to identify functional GWAS risk variants that show allele-specific open chromatin (ASoC), we nominated a putative AD causal SNP rs1532278 (T/C) of CLU that showed strong ASoC specifically in iPSC-derived excitatory neurons (iGlut). We found the AD protective allele T of rs1532278 elevated neuronal CLU and promoted neuron excitability. Transcriptomic analysis of iGlut (T/T vs. C/C) co-cultured with mouse astrocytes surprisingly showed allele T upregulated lipid synthesis and astrocytic lipid metabolism pathways. Further corroborative functional studies mechanistically tied allele T to CLU-facilitated neuron-glia lipid transfer and astrocytic lipid droplet (LD) formation. Interestingly, astrocytes with more LD were found to uptake less glutamate likely due to reactive oxygen species (ROS), which may contribute to CLU-promoted neuron excitability. Our study uncovered a previously unappreciated protective role of neuronal CLU in maintaining proper neuronal excitability through lipid-mediated neuron-glia communication.
2024-06-10 | GSE269153 | GEO
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
Project description:Microglia play important roles in maintaining brain homeostasis. The discovery of genetic variants in the genes encoding Apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2) as the strongest risk factors for Alzheimer’s disease (AD) highlights the importance of microglial biology in the brain. The sequence, structure and function of microglial proteins are poorly conserved across species, and this hampered the development of APOE and TREM2 targeting therapeutic strategies. One way to target APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs). In this study, we identified ASOs that selectively and potently reduce human APOE and TREM2 levels in human myeloid cells including iPSC-derived microglia. We demonstrated that a single bolus delivery of the ASOs in the mouse cerebrospinal fluid is sufficient for the ASO to be pharmacologically active and modify the phenotype of xenografted human microglia throughout the rodent brain for at least 4 weeks. This study is the first proof-of-concept that the expression of microglial genes can be modulated using ASOs in a dose-dependent manner in order to manipulate human microglia phenotypes in vivo, and demonstrates the utility of these ASOs both as research and therapeutic tools to modulate neuroinflammation.
2026-01-02 | GSE222331 | 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:Purpose: To study whether and how CLU rs11136000 associates with Alzheimer’s disease (AD) in astrocytes and affects their function. Methods: Different genotypes of astrocytes were differentiated from human isogenic iPSCs which used CRISPR/Cas9 editing, and total RNA was isolated and sequenced. Results: We identified 271 up-regulated genes (Fold-change ≥ 2, p<0.05) versus 176 down-regulated genes (Fold-change ≤ 0.5, p<0.05). Conclusion: CLU expression and IFN response were up-regulated in C/C astrocytes.
2023-06-23 | GSE193218 | GEO
Project description:To better define roles that microglia and astrocytes play in Alzheimer’s disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterize transcriptomes in these glial nuclei isolated post mortem from non-diseased control and neuropathologically-defined AD brains. Genes associated with AD risk were highly represented, especially in microglia. Transcriptome differences significantly correlated with immunohistochemical phospho-Tau (pTau) density included genetic risk genes for both microglia (APOE, BIN1, MS4A6A, PILRA) and astrocytes (APOE, CLU, MEF2C, IQCK). Pathways associated with the top differentially expressed genes in microglia included those related to proteostasis and immune modulation while those for astrocytes also included proteostasis, as well as stress response and metal ion homeostasis. Inferred regulons generated from co-expression networks implicated distinct transcriptional mechanisms associated with pTau for the two cell types. Data-driven sub-clustering revealed additional glial cellular heterogeneity. Our work provides a new resource, highlighting both potential causal mechanisms and protective glial responses in AD.
2021-10-01 | GSE160936 | GEO