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

Higher serum UA levels are associated with reduced AD risk in epidemiological studies. UA enhances microglial phagocytic capacity primarily by restoring CD36 and TREM2 receptor recycling that is impaired by Aβ exposure. Therapeutically, UA supplementation improves cognitive function and reduces neuropathology in AD mouse model by enhancing microglial Aβ clearance. 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. Higher serum UA levels are associated with reduced AD risk in epidemiological studies. UA enhances microglial phagocytic capacity primarily by restoring CD36 and TREM2 receptor recycling that is impaired by Aβ exposure. Therapeutically, UA supplementation improves cognitive function and reduces neuropathology in AD mouse model by enhancing microglial Aβ clearance. 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. Advanced Science, Volume 12, Issue 48, December 29, 2025.