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

Molecular neurodegeneration 2025

Zhao X, Li Y, Zhang S, Sudwarts A, Zhang H, Kozlova A, Moulton MJ, Goodman LD, Pang ZP, Sanders AR, Bellen HJ, Thinakaran G, Duan J

Abstract

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.

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