Complement C4b as a Key Mediator of Synaptic Loss and Cognitive Decline in Brain Aging.

IF 12 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-09-09 DOI:10.1016/j.ymthe.2025.09.005

Yi Zheng,Ting Liu,Lunan Luo,Feiyang Li,Cheng Tang,Changling Xu,Cheng Chen,Lu Yang,Ying Xiao,Ziyan Wang,Qing Yuan,Min Zheng,Hao Li,Jing Yang

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引用次数: 0

Abstract

Brain aging is a major risk factor for cognitive decline and neurodegenerative diseases, driven by synaptic loss, reduced synaptic function, and inflammation. However, the molecular mechanisms underlying these dysfunctions remain unclear. Here, we conducted comparative transcriptomic analyses of brain regions (cortex and hippocampus) and kidney tissues, a peripheral organ with documented age-related dysfunction. Our study uncovered common and tissue-specific aging molecular signatures, highlighting the complexity of aging-related gene expression dynamics. Notably, we identified complement component C4b as a key mediator linking inflammation to synaptic degeneration. Experimental modulation of C4b expression in aged neurons restored synaptic integrity and neuronal activity in vitro, while in vivo CRISPR-Cas13d-mediated suppression enhanced synaptic density and improved cognitive performance in aged mice. These findings establish C4b as a critical driver of age-associated cognitive decline and a promising therapeutic target for mitigating neurodegenerative changes.

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补体C4b是脑衰老中突触丧失和认知能力下降的关键介质。

脑老化是认知能力下降和神经退行性疾病的主要危险因素，由突触丧失、突触功能降低和炎症驱动。然而，这些功能障碍的分子机制尚不清楚。在这里，我们对大脑区域（皮质和海马体）和肾脏组织进行了比较转录组学分析，肾脏是一个有记录的与年龄相关的功能障碍的外周器官。我们的研究揭示了常见的和组织特异性的衰老分子特征，突出了衰老相关基因表达动态的复杂性。值得注意的是，我们发现补体成分C4b是连接炎症和突触变性的关键介质。在体外实验中，对衰老神经元中C4b表达的调节可恢复突触完整性和神经元活性，而在体内，crispr - cas13d介导的抑制可增强衰老小鼠的突触密度并改善认知表现。这些发现表明，C4b是年龄相关认知能力下降的关键驱动因素，也是缓解神经退行性变化的有希望的治疗靶点。

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

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.