a1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
a2 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
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.
(Received July 27 2011)
(Reviewed August 30 2011)
(Revised September 23 2011)
(Accepted September 28 2011)
(Online publication November 01 2011)
c1 Address for correspondence: B. S. Cha, M.D., Ph.D., Prof., Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul, Korea. Tel.: +82-2-2228-1962 Fax: +82-2-393-6884 Email: [email protected]
* These authors contributed equally to this work.