Sim_2025_Exp.Neurol__115271

Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) are known to ameliorate Alzheimer's disease (AD)-like pathology and cognitive decline through distinct mechanisms. In this study, we investigated how these antidiabetic drugs elevate ketone levels and subsequently reduce amyloid-beta (Abeta) and tau pathology via the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway in microglia, using a type 2 diabetes (T2D)-AD mouse model. Male C57BL/6 mice were fed a high-fat diet and injected with low doses of streptozotocin to establish a T2D-AD model. The mice were then treated with either SGLT2-i or DPP4-i. Our results revealed that both the inhibitors markedly enhanced brain ketone metabolism by upregulating key metabolic enzymes and transporters. They also reduced neuroinflammation by suppressing the expression of pro-inflammatory cytokines, such as IL-1beta, and increasing the expression of the anti-inflammatory cytokine IL-4. A critical mechanism for this anti-inflammatory effect involved the inhibition of the expression of the NLRP3 inflammasome, a key driver of neuroinflammation. Notably, SGLT2-i appeared to inhibit NLRP3 inflammasome expression by disrupting the pTau-CX3C1 interaction, whereas DPP4-i exerted its effects through the Abeta-TLR4-NF-kappaB pathway. Moreover, our results showed that both the inhibitors promoted a shift in microglial activation from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, as indicated by the changes in CD206 and CD86 expression. These findings suggest that SGLT2-i and DPP4-i provide neuroprotective benefits through multiple mechanisms, including enhanced ketone metabolism, reduced neuroinflammation, and modulation of microglial activity in T2D-AD mouse model. This research offers a scientific basis for considering these inhibitors as potential therapeutic agents for neurodegenerative diseases, particularly in cognitive impairment patients with metabolic dysfunction.