Alzheimer’s Disease Protective Allele of Clusterin Modulates Neuronal Excitability Through Lipid-Droplet-Mediated Neuron-Glia Communication

Authors

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

Language

English

Publication Date

5-3-2025

Journal

Molecular Neurodegeneration

DOI

10.1186/s13024-025-00840-1

PMID

40319306

PMCID

PMC12049787

PubMedCentral® Posted Date

5-3-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Clusterin, Neurons, Animals, Alzheimer Disease, Mice, Neuroglia, Induced Pluripotent Stem Cells, Lipid Droplets, Alleles, Humans, Genome-Wide Association Study, Cell Communication, Astrocytes, Polymorphism, Single Nucleotide, Alzheimer’s disease, Clusterin, Protective allele, Lipid droplets, Neuron excitability, Allele-specific open chromatin, Genome-wide association study, IPSC, Neuron-glia lipid transfer

Published Open-Access

yes

Recommended Citation

Zhao, Xiaojie; Li, Yan; Zhang, Siwei; et al., "Alzheimer’s Disease Protective Allele of Clusterin Modulates Neuronal Excitability Through Lipid-Droplet-Mediated Neuron-Glia Communication" (2025). Duncan NRI Faculty and Staff Publications. 143.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/143