Solanesol Improves Diabetes-Associated Cognitive Dysfunction in Mice Alongside Metabolic, Hippocampal and Gut-Related Changes

Background/Objectives: Diabetes-associated cognitive dysfunction (DACD) remains difficult to treat, and improved peripheral metabolism does not necessarily restore cognition. We investigated solanesol, a plant-derived long-chain polyisoprenoid alcohol, in a high-fat-diet (HFD) mouse model. Methods: Male C57BL/6 mice received an HFD for 24 weeks, followed by 6 weeks of solanesol (10, 20 or 30 mg/kg/day) or rosiglitazone (20 mg/kg/day). Metabolic indices, Morris water maze and novel object recognition performance, hippocampal and ileal morphology, hippocampal transcriptomics, faecal metagenomics and untargeted metabolomics were assessed. Results: HFD feeding induced obesity, hyperglycaemia, hyperinsulinaemia, insulin resistance and impaired spatial and recognition memory. Rosiglitazone improved insulin sensitivity without a detectable cognitive benefit. Solanesol reduced HOMA-IR at all tested doses; reductions in body weight and fasting glucose were observed at the highest dose (SNL-30). Cognitive responses differed by endpoint and were most consistent at the medium and high doses. SNL-30 was associated with a qualitative improvement in hippocampal and ileal morphology, increased hippocampal Apoc3 and Pon1 expression and changes in the gut microbiota and faecal metabolome. Faecal microbial and metabolite profiles covaried. Conclusions: Solanesol improved metabolic and selected cognitive outcomes in HFD-fed mice, with the broadest response at the highest tested dose. Solanesol is a candidate for further preclinical study in DACD.