Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.

IF 14.1 1区材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Advanced Science Pub Date : 2025-10-06 DOI:10.1002/advs.202510270

De Xie, Qiuyang Zheng, Jiaming Lv, Qian Zhang, Zhiwei Cui, Shuai Huang, Wei Yu, Binyang Chen, Wanling Que, Shanpan Fu, Yuemei Xi, Jiayu Chen, Xueling Ye, Shuyi Chen, Hairong Zhao, Tetsuya Yamamoto, Hidenori Koyama, Xin Wang, Jidong Cheng

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Abstract

Epidemiological studies have linked uric acid (UA), the end product of purine metabolism in humans, with reduced Alzheimer's disease (AD) risk. Decreased serum UA levels are observed in AD patients versus age-matched controls, while upstream purine metabolites remained unchanged. In 5×FAD mice, two months of UA supplementation improved cognitive function and reduced amyloid plaque burden. Mechanistically, UA enhances microglial amyloid-β (Aβ) phagocytosis and induces transcriptional reprogramming in AD mouse microglia, characterized by upregulated phagocytic pathways and attenuated inflammatory responses. UA treatment restored the recycling of Aβ receptors CD36 and TREM2 in microglia, enhanced lysosomal biogenesis, and facilitated Aβ degradation. These findings identify UA as a critical endogenous modulator of microglial Aβ processing and suggest exploring UA supplementation as a therapeutic strategy for AD.

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尿酸作为阿尔茨海默病小胶质细胞功能和淀粉样蛋白清除的内源性调节剂。

流行病学研究已将尿酸（UA）与降低阿尔茨海默病（AD）风险联系起来，尿酸是人体嘌呤代谢的最终产物。与年龄匹配的对照组相比，AD患者血清UA水平下降，而上游嘌呤代谢物保持不变。在5×FAD小鼠中，两个月的UA补充改善了认知功能并减少了淀粉样斑块负担。在机制上，UA增强AD小鼠小胶质细胞淀粉样蛋白-β (Aβ)吞噬并诱导转录重编程，其特征是吞噬途径上调和炎症反应减弱。UA处理恢复了小胶质细胞中Aβ受体CD36和TREM2的循环，增强了溶酶体的生物发生，促进了Aβ的降解。这些发现确定了UA是小胶质细胞a β加工的关键内源性调节剂，并建议探索UA补充作为AD的治疗策略。

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

Advanced Science CHEMISTRY, MULTIDISCIPLINARYNANOSCIENCE &-NANOSCIENCE & NANOTECHNOLOGY

CiteScore

18.90

自引率

2.60%

发文量

1602

审稿时长

1.9 months

期刊介绍： Advanced Science is a prestigious open access journal that focuses on interdisciplinary research in materials science, physics, chemistry, medical and life sciences, and engineering. The journal aims to promote cutting-edge research by employing a rigorous and impartial review process. It is committed to presenting research articles with the highest quality production standards, ensuring maximum accessibility of top scientific findings. With its vibrant and innovative publication platform, Advanced Science seeks to revolutionize the dissemination and organization of scientific knowledge.