Investigating the Therapeutic Potential of Uric Acid in Alzheimer's Disease: Insights from the cGMP-PKG Signaling Pathway

Background : Alzheimer's disease (AD) is characterized by neuroinflammation and oxidative stress, both contributing to disease progression. Uric acid (UA) has emerged as a potential therapeutic agent due to its anti-inflammatory and antioxidative properties. However, the precise mechanisms underlying UA's role in AD pathogenesis remain unclear. Methods: BV2 microglial cells were subjected to treatments with UA, lipopolysaccharide (LPS), or a combination of both. Analyses of gene expression profiling, protein assessment, ELISA, ROS assays, and proteomic analysis were performed. Statistical analyses involved one-way ANOVA followed by Dunnett's multiple comparison tests and Student’s unpaired t-test for group comparisons. Results : UA treatment markedly suppressed LPS-induced upregulation of NF-𝜅B and NLRP3 mRNA expression (p < 0.001). Inflammatory cytokine release (IL-1β and TNF𝜶) was reduced by up to 50% (p < 0.05) with UA treatment, while oxidative stress was mitigated, evidenced by an 84% reduction in ROS levels (p < 0.001) and a 32% increase in antioxidant enzyme activity (p < 0.01). Proteomic analysis unveiled significant alterations in key signaling pathways pertinent to AD pathology, including downregulation of cholesterol metabolism (p < 0.05) and upregulation of cGMP-PKG (p < 0.001) and Wnt signaling pathways (p < 0.001). Notably, UA treatment induced increased expression of Atp2b4, a pivotal regulator of calcium homeostasis, suggesting its potential role in mediating the observed antioxidative effects. Conclusions : UA exhibits promising anti-inflammatory and antioxidative effects in BV2 microglial cells, underscoring its potential as a therapeutic avenue for AD. These findings offer valuable insights into UA's molecular mechanisms and advocate for further investigation to validate its clinical efficacy in managing AD. Understanding UA's role in modulating neuroinflammatory pathways and oxidative stress could pave the way for novel therapeutic interventions in AD management.