Sarsasapogenin attenuates Alzheimer-like encephalopathy in diabetes

Background: A crosstalk exists between diabetes and Alzheimer's disease (AD), and diabetic encephalopathy displays AD-like disorders. Sarsasapogenin (Sar) has strong anti-inflammatory efficacy, showing neuroprotection and memory-enhancement effects. Purpose: This study aims to verify the ameliorative effects of Sar on diabetic encephalopathy in vivo and in vitro, and to clarify the mechanisms from attenuation of AD-like pathology. Methods: Streptozotocin-induced type 1 diabetic rats and high glucose-cultured SH-SY5Y cells were used in this study. After Sar treatment (20 and 60 mg/kg) for consecutive 9 weeks, Morris water maze and novel object recognition tasks were performed. Hematoxylin-eosin staining was used for examining loss of neurons in CA1 area and ki67 expression for reflecting neurogenesis in DG area of hippocampus. A beta production pathway and tau phosphorylation kinase cascade were examined in these two models. Results: Sar improved learning and memory ability, loss of neurons and reduction of neurogenesis in the hippocampus of diabetic rats. Moreover, Sar suppressed A beta overproduction due to up-regulation of BACE1 in protein and mRNA and tau hyperphosphorylation from inactivation of AKT/GSK-3 beta cascade in the hippocampus and cerebral cortex of diabetic rats and high glucose-cultured SH-SY5Y cells, and PPAR gamma antagonism abolished the effects of Sar on key molecules in the two pathways. Additionally, it was found that high glucose-stimulated A beta overproduction was prior to tau hyperphosphorylation in neurons. Conclusion: Sar alleviated diabetic encephalopathy, which was obtained through inhibitions of A beta overproduction and tau hyperphosphorylation mediated by the activation of PPAR gamma signaling. Hence, Sar is a good candidate compound for AD-like disorders.