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Alzheimer's Association International Conference 2026
July 12-15, 2026 | London, United Kingdom, and Online
4010
Alzheimer’s Protective CLU Allele Modulates Neuronal Excitability Via Lipid-droplet Neuron-glia Communication
Poster Presenter
Authors
Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew Moulton, Lindsey Goodman, Zhiping Pang, Alan Sanders, Hugo Bellen, Gopal Thinakaran, Jubao Duan
Affiliations
1. Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA; 2. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA;3.Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong Province, China;, Department of Bioinformatics, Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong Province, China, 1. Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA; 2. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA;, 1.Byrd Alzheimer’s Center and Research Institute, University of South Florida, Tampa, FL 33613, USA; 2. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33160, USA;, Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA, 1. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; 2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;, Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA, 1. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA; 2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; 3. Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA;
Part of Topic
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.
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