title: 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.
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.
authors: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Jae Hoon
authors: JH
authors: Moon
authors: Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors: Hyung Jun
authors: HJ
authors: Kim
authors: Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors: Ae Hee
authors: AH
authors: Yang
authors: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Hyun Min
authors: HM
authors: Kim
authors: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Byung-Wan
authors: BW
authors: Lee
authors: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Eun Seok
authors: ES
authors: Kang
authors: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Hyun Chul
authors: HC
authors: Lee
authors: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Bong Soo
authors: BS
authors: Cha
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone