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