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

Autor:	Zhao X; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA., Li Y; Department of Bioinformatic, Nanjing Medical University, Nanjing, Jiangsu, 211166, China., Zhang S; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA., Sudwarts A; Byrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL 33613, USA.; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33160, USA., Zhang H; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA., Kozlova A; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA., Moulton MJ; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Goodman LD; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Pang ZP; Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA., Sanders AR; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA., Bellen HJ; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Thinakaran G; Byrd Alzheimer's Center and Research Institute, University of South Florida, Tampa, FL 33613, USA.; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33160, USA., Duan J; Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 15. Date of Electronic Publication: 2024 Aug 15.
DOI:	10.1101/2024.08.14.24312009
Abstrakt:	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 remain largely unknown. For a strong AD-associated locus near Clusterin ( CLU ), we tied an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. We identified a putative causal SNP of CLU that impacts neuron-specific chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal CLU and promoting neuron excitability. Transcriptomic analysis and functional studies in induced pluripotent stem cell (iPSC)-derived neurons co-cultured with mouse astrocytes show that neuronal CLU facilitates neuron-to-glia lipid transfer and astrocytic lipid droplet formation coupled with reactive oxygen species (ROS) accumulation. These changes cause astrocytes to uptake less glutamate thereby altering neuron excitability. Our study provides insights into how CLU confers resilience to AD through neuron-glia interactions. Competing Interests: Declaration of interests The authors declare no competing interests.
Databáze:	MEDLINE
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