The effect of rosiglitazone on LRP1 expression and amyloid β uptake in human brain microvascular endothelial cells: a possible role of a low-dose thiazolidinedione for dementia treatment.

Thiazolidinediones, such as rosiglitazone or pioglitazone, are anti-diabetic agents that have been expected to show a beneficial effect in Alzheimer's disease (AD) because of their anti-inflammatory effect. However, these agents have failed to show a significant beneficial effect on AD in recent clinical trials. Here, we suggest that low-dose rosiglitazone treatment, and not the conventional doses, has an amyloid β (Aβ)-clearing effect by increasing LRP1, an Aβ outward transporter in the blood-brain barrier. Rosiglitazone up-regulated LRP1 mRNA and protein expression and LRP1 promoter activity in human brain microvascular endothelial cells (HBMECs). Aβ uptake through LRP1 in HBMECs was also increased by rosiglitazone. This increase in LRP1 and Aβ uptake was observed in up to 10 nm rosiglitazone concentration. At concentrations above 20 nm rosiglitazone, the LRP1 expression and Aβ uptake in HBMECs were not altered. The possible mechanism of this unusual dose response is discussed. This study suggests a new therapeutic application of thiazolidinediones for AD at a much lower dose than the doses used for diabetes treatment.ope

Upregulation of hepatic LRP1 by rosiglitazone: a possible novel mechanism of the beneficial effect of thiazolidinediones on atherogenic dyslipidemia

Hepatic LDL receptor-related protein 1 (LRP1) plays a role in the clearance of circulating remnant lipoproteins. In this study, we investigated the effect of rosiglitazone treatment on the expression and function of hepatic LRP1. HepG2 cells were incubated with various concentrations of rosiglitazone. Male Long-Evans Tokushima Otsuka (LETO) rats and Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats were treated with rosiglitazone for 5 weeks. The expression and function of LRP1 in HepG2 cells and liver samples of rats were analyzed. LRP1 mRNA and protein expressions were increased by 0.5 and 5  μM rosiglitazone in HepG2 cells. However, at concentrations above 50  μM rosiglitazone, LRP1 mRNA and protein expressions did not change compared with those in nontreated cells. Reporter assay showed that 0.5 and 5  μM rosiglitazone increased the transcriptional activity of the LRP1 promoter in HepG2 cells. The uptake of apolipoprotein E through LRP1 in HepG2 cells was also increased by rosiglitazone. Hepatic LRP1 was reduced in OLETF rats compared with that of LETO rats and rosiglitazone treatment increased hepatic LRP1 in OLETF rats. A high glucose condition (25  mM glucose in culture media) reduced the expression of LRP1 in HepG2 cells, and this reduced LRP1 expression was recovered with rosiglitazone. In conclusion, our data suggest that decreased hepatic LRP1 in a diabetic condition is associated with the development of atherogenic dyslipidemia and that increased hepatic LRP1 by thiazolidinediones could contribute to an improvement in atherogenic lipid profiles in diabetic patients.ope