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CLU alleviates Alzheimer’s disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density [RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE294133 | GEO | 2025/04/28

REPOSITORIES: GEO

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CLU alleviates Alzheimer’s disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density [scRNA-seq]

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

Alzheimer’s Disease Protective Allele of CLU Promotes Neuron Excitability, Neuron-glia Lipid Transfer and Astrocytic Lipid Droplets via neuronal CLU

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

SORL1 regulates APOE and CLU levels in human neurons

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

Glycosylated clusterin species facilitate amyloid beta toxicity in human neurons.

Project description:Clusterin (CLU) is one of the most significant genetic risk factors for late onset Alzheimer’s disease. Numerous studies have now demonstrated that CLU-AD mutations and amyloid-β (Aβ) treatment alter the trafficking and localisation of glycosylated CLU. iPSCs with altered CLU trafficking were generated following the removal of CLU exon 2 by CRISPR/Cas9 gene editing. Neurons were generated from control, unedited and exon 2 -/- iPSCs and were incubated with aggregated Aβ peptides. Changes in cell death and neurite length were quantified to determine if altered CLU protein trafficking influenced neuronal sensitivity to Aβ.

2022-07-05 | GSE207466 | GEO

Clu

Project description:Rattus norvegicus Clu, clusterin [Source:RGD Symbol;Acc:3907], is differentially expressed in 35 experiment(s);

| ENSRNOG00000016460 | ExpressionAtlas

Clu

Project description:Rattus norvegicus Clu, clusterin [Source:RGD Symbol;Acc:3907], is expressed in 10 baseline experiment(s);

| ENSRNOG00000016460 | ExpressionAtlas

CLU

Project description:Sus scrofa CLU, clusterin [Source:VGNC Symbol;Acc:VGNC:86790], is expressed in 8 baseline experiment(s);

| ENSSSCG00000009668 | ExpressionAtlas

CLU

Project description:Macaca mulatta CLU, clusterin [Source:VGNC Symbol;Acc:VGNC:71269], is expressed in 3 baseline experiment(s);

| ENSMMUG00000021516 | ExpressionAtlas

CLU

Project description:Oryctolagus cuniculus CLU, clusterin [Source:HGNC Symbol;Acc:HGNC:2095], is expressed in 1 baseline experiment(s);

| ENSOCUG00000005985 | ExpressionAtlas

CLU

Project description:Homo sapiens CLU, clusterin [Source:HGNC Symbol;Acc:HGNC:2095], is expressed in 66 baseline experiment(s);

| ENSG00000120885 | ExpressionAtlas

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