Lish Alexandra M, Grogan Elyssa F L, Benoit Courtney R, Pearse Richard V, Heuer Sarah E, Luquez Tain, Orme Gwendolyn A, Galle Paige C, Milinkeviciute Giedre, Green Kim N, Alexander Kellianne D, Fancher Seeley B, Stern Andrew M, Fujita Masashi, Bennett David A, Seyfried Nicholas T, De Jager Philip L, Menon Vilas, Young-Pearse Tracy L
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Center for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
Neuron. 2025 Jun 18;113(12):1925-1946.e11. doi: 10.1016/j.neuron.2025.03.034. Epub 2025 Apr 30.
Genetic studies implicate clusterin (CLU) in the pathogenesis of Alzheimer's disease (AD), yet its precise molecular impact remains unclear. Through unbiased proteomic profiling and functional validation in CLU-deficient astrocytes, we identify increased nuclear factor κB (NF-κB)-dependent signaling and complement C3 secretion. Reduction of astrocyte CLU induced microglia-dependent modulation of extracellular apolipoprotein E (APOE) and phosphorylated tau, as well as increased microglial phagocytosis and reduced synapse numbers. By integrating mouse and human cellular models with comprehensive analyses of human plasma and brain tissue, we demonstrate that CLU AD-risk alleles are associated with reduced CLU protein and heightened inflammatory profiles. These findings establish a mechanistic link between AD genetic risk factors, astrocyte reactivity, and microglia-mediated effects on synaptic integrity. Collectively, these results support a model in which CLU upregulation in response to neuropathology is associated with maintenance of cognitive function, while diminished astrocyte CLU levels heighten disease susceptibility.
基因研究表明簇集蛋白（CLU）与阿尔茨海默病（AD）的发病机制有关，但其确切的分子影响仍不清楚。通过在CLU缺陷型星形胶质细胞中进行无偏蛋白质组分析和功能验证，我们发现核因子κB（NF-κB）依赖性信号传导增加和补体C3分泌增加。星形胶质细胞CLU的减少诱导了小胶质细胞依赖性的细胞外载脂蛋白E（APOE）和磷酸化tau的调节，以及小胶质细胞吞噬作用增加和突触数量减少。通过将小鼠和人类细胞模型与对人类血浆和脑组织的综合分析相结合，我们证明CLU AD风险等位基因与CLU蛋白减少和炎症特征增强有关。这些发现建立了AD遗传风险因素、星形胶质细胞反应性和小胶质细胞对突触完整性的介导作用之间的机制联系。总体而言，这些结果支持了一个模型，即对神经病理学做出反应的CLU上调与认知功能的维持有关，而星形胶质细胞CLU水平降低会增加疾病易感性。
