Sotagliflozin improves cognitive deficits and attenuates neuroinflammation of Alzheimer's disease.

Effective treatments for Alzheimer's disease (AD) are limited. Due to shared pathological mechanisms between AD and diabetes, antidiabetic drugs like sodium-glucose cotransporter-2 inhibitors (SGLT2is) are potential therapeutic options. Although SGLT2is have shown cognitive benefits in diabetes models, their effects in AD models are not fully established. This study aimed to evaluate the therapeutic effects of sotagliflozin (Sota), an SGLT2i, in both in vivo and in vitro AD models. The network pharmacology analysis was used to predict the potential targets and pathways of Sota. And we selected 6-month-old APP/PS1 transgenic mice to investigate the effects of Sota. Cognitive function was assessed using the Morris water maze test. Immunohistochemistry and immunofluorescence were employed to quantify amyloid-beta (Aβ) plaque deposition in the hippocampal or cortex and analyze neuronal loss. Additionally, amyloid β oligomers induction and microglial cells were used to evaluate the effects of Sota on the release of pro-inflammatory mediators and to investigate the underlying mechanisms. In vivo, Sota treatment improved cognitive impairments, reduced pro-inflammatory cytokines, inhibited microglial activation, and promoted neuronal survival. In vitro, Sota mitigated Aß oligomer-induced toxicity in microglial cells by decreasing reactive oxygen species and pro-inflammatory cytokine release. Mechanistically, Sota treatment was associated with suppression of extracellular signal-regulated kinase (ERK) signaling. Our findings suggest that Sota improved cognitive impairment and attenuates neuroinflammation in AD. Sota may be a promising candidate for the treatment of AD.