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

  • Adv Sci (Weinh). 2025 Oct 6:e10270. doi: 10.1002/advs.202510270.
De Xie  1  2  3 ,  Qiuyang Zheng  4 ,  Jiaming Lv  1  2 ,  Qian Zhang  1  2 ,  Zhiwei Cui  5 ,  Shuai Huang  1  2 ,  Wei Yu  1  2 ,  Binyang Chen  1  2 ,  Wanling Que  1  2 ,  Shanpan Fu  1  2 ,  Yuemei Xi  1  2 ,  Jiayu Chen  1  2 ,  Xueling Ye  1  2 ,  Shuyi Chen  1  2 ,  Hairong Zhao  1  2 ,  Tetsuya Yamamoto  6 ,  Hidenori Koyama  7 ,  Xin Wang  4 ,  Jidong Cheng  1  2  7
Affiliations
  • 1. Department of Internal Medicine, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
  • 2. Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiamen, Fujian, 361102, China.
  • 3. Department of Geriatrics, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, 710061, China.
  • 4. State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Shenzhen Research Institute, Xiamen University, Xiamen, Fujian, 361102, China.
  • 5. The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
  • 6. Department of Health Evaluation Center, Osaka Gyoumeikan Hospital, Osaka, 554-0012, Japan.
  • 7. Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan.
PMID: 41051385 DOI: 10.1002/advs.202510270
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.

Keywords
Alzheimer's disease; amyloid‐β; microglia; uric acid.
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