Deer Antler Uridine Regulates Glycolysis in Microglia via HSP90/HIF-1α to Improve Cognitive Impairment in Alzheimer's Disease Mice.

AIM

To investigate the role and mechanism of uridine (URI), an active component in deer antler, in improving cognitive impairment in Alzheimer's disease (AD) mice.

METHOD

The APP/PS1 mouse model was used for AD. After URI gavage administration, cognitive behavioral changes in mice were detected using the Morris water maze, eight-arm maze, and novel object recognition tests. Levels of inflammatory cytokines and lactate, pyruvate in the cortex were measured. The proportions of IBA-1 and CD86 cells in tissues were detected, and the expression of key glycolysis proteins was examined. Network pharmacology was employed to analyze the targets of URI-AD-glycolysis. AAV-CMV-shHSP90 was injected to knock down brain HSP90 levels to further explore the anti-AD mechanism of URI. In vitro, primary microglia were used to detect the proportion of CD86+ M1 cells and glycolysis levels.

RESULT

URI can improve cognitive impairment in AD mice, with significant changes in cognitive ability and behavior. URI reduces glycolysis levels, the proportion of M1 cells (CD86+), and the activation degree of microglia, while inhibiting the activation of HSP90-HIF-1α. Network pharmacology analysis revealed that HSP90 is a major target of URI. When HSP90 is inhibited, the effect of URI is diminished. In vitro experiments showed that URI can inhibit the M1 polarization of microglia and reduce glycolysis levels.

CONCLUSION

URI can inhibit microglial glycolysis and M1 polarization via HSP90/HIF-1α, thereby improving cognitive behavioral deficits in AD mice due to neuroinflammation. Uridine in deer antler is a novel small molecule for anti-AD.