Zhao Xiaojie, Li Yan, Zhang Siwei, Sudwarts Ari, Zhang Hanwen, Kozlova Alena, Moulton Matthew J, Goodman Lindsey D, Pang Zhiping P, Sanders Alan R, Bellen Hugo J, Thinakaran Gopal, Duan Jubao
Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA.
medRxiv. 2024 Aug 15:2024.08.14.24312009. doi: 10.1101/2024.08.14.24312009.
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 (), 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 that impacts neuron-specific chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal 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.
阿尔茨海默病（AD）的全基因组关联研究（GWAS）已经确定了大量风险位点。然而，疾病变异体/基因及其潜在机制在很大程度上仍然未知。对于位于（）附近的一个与AD强相关的位点，我们将一个AD保护性等位基因与神经元CLU通过脂质介导的神经元-胶质细胞通讯促进神经元兴奋性的作用联系起来。我们鉴定出一个推定的因果单核苷酸多态性（SNP），它影响神经元特异性染色质对转录因子的可及性，AD保护性等位基因上调神经元CLU并促进神经元兴奋性。在与小鼠星形胶质细胞共培养的诱导多能干细胞（iPSC）衍生神经元中的转录组分析和功能研究表明，神经元CLU促进神经元向胶质细胞的脂质转移以及星形胶质细胞脂滴形成并伴有活性氧（ROS）积累。这些变化导致星形胶质细胞摄取较少的谷氨酸，从而改变神经元兴奋性。我们的研究为CLU如何通过神经元-胶质细胞相互作用赋予对AD的抵抗力提供了见解。
