CLU alleviates Alzheimer's disease-relevant processes by modulating astrocyte reactivity and microglia-dependent synaptic density.

IF 14.7 1区医学 Q1 NEUROSCIENCES

Neuron Pub Date : 2025-04-22 DOI:10.1016/j.neuron.2025.03.034

Alexandra M Lish, Elyssa F L Grogan, Courtney R Benoit, Richard V Pearse, Sarah E Heuer, Tain Luquez, Gwendolyn A Orme, Paige C Galle, Giedre Milinkeviciute, Kim N Green, Kellianne D Alexander, Seeley B Fancher, Andrew M Stern, Masashi Fujita, David A Bennett, Nicholas T Seyfried, Philip L De Jager, Vilas Menon, Tracy L Young-Pearse

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引用次数: 0

Abstract

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.

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CLU通过调节星形胶质细胞反应性和小胶质细胞依赖的突触密度来减轻阿尔茨海默病相关过程。

遗传学研究表明簇蛋白（CLU）与阿尔茨海默病（AD）的发病机制有关，但其确切的分子作用尚不清楚。通过无偏倚的蛋白质组学分析和clu缺陷星形胶质细胞的功能验证，我们发现核因子κB （NF-κB）依赖性信号和补体C3分泌增加。星形胶质细胞CLU的减少诱导了细胞外载脂蛋白E （APOE）和磷酸化tau蛋白的小胶质依赖性调节，以及小胶质吞噬作用的增加和突触数量的减少。通过将小鼠和人类细胞模型与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蛋白减少和炎症谱升高有关。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介导的突触完整性效应之间的机制联系。总的来说，这些结果支持一个模型，即CLU在神经病理反应中的上调与认知功能的维持有关，而星形胶质细胞CLU水平的降低会增加疾病的易感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuron 医学-神经科学

CiteScore

24.50

自引率

3.10%

发文量

382

审稿时长

1 months

期刊介绍： Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.