Rosiglitazone Attenuates Diabetes-Induced Cognitive Function Via Altering Hippocampal IRS1/AKT Signaling Pathways

Background:Several research groups have begun to associate the Alzheimer Disease (AD) to Diabetes Mellitus (DM). DM also increases the risk of developing AD. But the mechanism linking DM and AD is not clear. Insulin resistance is a critical feature of DM. And it is important to note that insulin receptor activity was reduced in the AD brain. The present study was to elucidate the pathological mechanism of diabetes-induced AD and to identify alteration in key molecular components related to memory formation and insulin signaling in the hippocampus after rosiglitazone(RSG) was injected into the diabetic mice to test whether cognitive dysfunction was pharmacologically reversed by regulation of RSG.Methods:1) The SD rats were randomly divided into two groups (n=8):(1) STZ-treated group (STZ), for which rats received intraperitoneal injection of 50mg/kg STZ; (2) Saline-treated group (Ctrl), which received intraperitoneally the same volume of saline. The rats were maintained on a standard chow diet under a 12 h light/dark cycle, and were free access to water. The brain tissue was rapidly removed from the skull for hippocampus dissection. Western blot were implemented to evaluate the following proteins:BACE1, P-IRS1, P-Akt and Total-IRS1, Total-Akt in hippocampal tissues. RT-PCR was performed to measure APP mRNA level. The Aβ1-40 levels were detected by ELISA Kit.2) The age-matched mice were divided into three groups (n=18):Saline-treated WT mice (WT-Saline); Saline-treated ob/ob mice (ob/ob-Saline) and RSG-treated ob/ob mice (ob/ob-RSG) through intraperitoneal injection of RSG daily for 10 days. Body weight was also monitored during the experiment. The glucose levels were measured during the intraperitoneal injection period. Novel object recognition was performed before mice were sacrificed. Western blot were implemented to evaluate the following proteins:Bacel, P-Tau, P-IRS1, IRS1, P-Akt and Akt in hippocampal tissues. The Aβ1-40 levels were detected by ELISA Kit.Results:1) The body weight was lower and the blood glucose levels were significantly higher in STZ-treated rats than that of the control rat Compared with the control group, the mRNA expression of APP was significantly increased in STZ-treated rats. The protein levels of Bacel and Aβ, which were critical hallmarks of cognitive dysfunction and amyloid deposits, were increased in STZ-treated rats. Furthermore, hippocampal P-IRS1/IRS1 and P-Akt/Akt ratios were down-regulated, demonstrating that insulin signaling pathways were impaired in STZ-treated rats.2) The blood glucose levels were significantly reduced in ob/ob-RSG compared with ob/ob-Saline, suggesting improved glucose metabolism. RSG treatment led to an increase in hippocampus-dependent cognition of ob/ob mice according to the novel object recognition. The proteins levels of Bacel, P-Tau and Aβ were lowered in RSG-treated ob/ob mice. Furthermore, RSG treatment up-regulated hippocampal P-IRS1/IRS1 and P-Akt/Akt ratio, demonstrating that insulin signaling pathways were enhanced in ob/ob-RSG mice.Conclusion:1) The abnormally increased Aβ in diabetic rats may results from impaired insulin signaling pathways in the hippocampus.2) Rosiglitazone ameliorates cognitive deficits in ob/ob mice through up-regulating insulin signaling pathways in the hippocampus.