Moon, Jae Hoon; Kim, Hyung Jun; Yang, Ae Hee; Kim, Hyun Min; Lee, Byung-Wan; Kang, Eun Seok; Lee, Hyun Chul; Cha, Bong Soo
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)
2012Feb ; 15 ( 1 ) :135-42.
PMID : 22040807
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Moon, Jae Hoon - Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Kim, Hyung Jun - Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Yang, Ae Hee - Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Kim, Hyun Min - Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Lee, Byung-Wan - Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Kang, Eun Seok - Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Lee, Hyun Chul - Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
Cha, Bong Soo - Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
ABSTRACT
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.
Alzheimer's disease, amyloid ? blood–brain barrier, LRP1, thiazolidinedione
MESH
Amyloid beta-Peptides/*metabolism, Anti-Inflammatory Agents/administration & dosage, Blood-Brain Barrier/drug effects/physiopathology, Brain/blood supply/*drug effects/physiopathology, Dose-Response Relationship, Drug, Endothelial Cells/*drug effects/physiology, Gene Expression/drug effects, Humans, Low Density Lipoprotein Receptor-Related Protein-1/genetics/*metabolism, Microvessels/drug effects/physiopathology, Neuroprotective Agents/*administration & dosage, Promoter Regions, Genetic, RNA, Messenger/metabolism, Thiazolidinediones/*administration & dosage
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