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Background <p>Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied.</p> Methods <p>Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation.</p> Results <p>We identified a putative causal SNP of <i>CLU</i> that impacted neuronal chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal <i>CLU</i> and promoting neuron excitability. And, neuronal CLU facilitated neuron-to-glia lipid transfer and astrocytic lipid droplet formation coupled with reactive oxygen species (ROS) accumulation. These changes caused astrocytes to uptake less glutamate thereby altering neuron excitability.</p> Conclusions <p>For a strong AD-associated locus near <i>Clusterin</i> (<i>CLU</i>), we connected an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. Our study provides insights into how CLU confers resilience to AD through neuron-glia interactions.</p>

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Alzheimer’s disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月3日

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  • Xiaojie Zhao,
  • Yan Li,
  • Siwei Zhang,
  • Ari Sudwarts,
  • Hanwen Zhang,
  • Alena Kozlova,
  • Matthew J. Moulton,
  • Lindsey D. Goodman,
  • Zhiping P. Pang,
  • Alan R. Sanders,
  • Hugo J. Bellen,
  • Gopal Thinakaran,
  • Jubao Duan

摘要

Background

Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied.

Methods

Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation.

Results

We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal CLU and promoting neuron excitability. And, neuronal CLU facilitated neuron-to-glia lipid transfer and astrocytic lipid droplet formation coupled with reactive oxygen species (ROS) accumulation. These changes caused astrocytes to uptake less glutamate thereby altering neuron excitability.

Conclusions

For a strong AD-associated locus near Clusterin (CLU), we connected an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. Our study provides insights into how CLU confers resilience to AD through neuron-glia interactions.