title: 1,25-Dihydroxyvitamin D3 regulates expression of LRP1 and RAGE in vitro and in vivo, enhancing Aβ1-40 brain-to-blood efflux and peripheral uptake transport.
abstract: Alzheimer's disease (AD) is characterized by the accumulation and deposition of plaques of amyloid-β (Aβ) peptide in the brain. Growing epidemiological and experimental studies have shown that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts neuroprotection against AD. However, the underlying mechanisms of the action remain unclear. Since Aβ clearance plays a crucial role in Aβ balance in the brain, the aim of the present study was to investigate potential effects of 1,25(OH)2D3 on Aβ1-40, the major soluble oligomeric form of Aβ, clearance via transport across blood-brain barrier (BBB) mediated by low-density lipoprotein receptor-related protein 1 (LRP1) (efflux) and receptor for advanced glycation end products (RAGE) (influx) and peripheral uptake by liver mediated by LRP1. We identified colocalization of LRP1 and RAGE at BBB of mice, established an in vitro BBB model by culturing monolayer mouse brain microvascular endothelial cell line (bEnd.3) cells under hypoxia and observed that 1,25(OH)2D3 treatment enhanced Aβ1-40 efflux across the BBB model and uptake by HepG2 cells. After 1,25(OH)2D3 exposure, LRP1 expression was increased significantly both in vivo and in vitro, and RAGE expression was reduced in the in vitro BBB model but not in microvascular endothelial cells of mice hippocampus. Additionally, we explored the correlation between the corresponding effects of 1,25(OH)2D3 and its nuclear hormone receptor vitamin D receptor (VDR) level. We found that VDR expression was upregulated after 1,25(OH)2D3 treatment both in vivo and in vitro. Collectively, our finding that 1,25(OH)2D3 reduces cerebral Aβ1-40 level by increasing Aβ1-40 brain-to-blood efflux and peripheral uptake through regulating LRP1 and RAGE could shed light on the mechanism of 1,25(OH)2D3 neuroprotection against AD. And the action of 1,25(OH)2D3 might be associated with the VDR pathway.
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha 410011, China; School of Pharmaceutical Sciences, Central South University, Changsha 410011, China.
authors.forename: Y-X
authors.initials: YX
authors.lastname: Guo
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha 410011, China; School of Pharmaceutical Sciences, Central South University, Changsha 410011, China.
authors.forename: L-Y
authors.initials: LY
authors.lastname: He
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha 410011, China; School of Pharmaceutical Sciences, Central South University, Changsha 410011, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha 410011, China; School of Pharmaceutical Sciences, Central South University, Changsha 410011, China.
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha 410011, China; School of Pharmaceutical Sciences, Central South University, Changsha 410011, China.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: Institute of Clinical Pharmacy & Pharmacology, Second Xiangya Hospital, Central South University, Changsha 410011, China. Electronic address: pwx.csu@163.com.
authors.forename: W-X
authors.initials: WX
authors.lastname: Peng
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C000593871:AGER protein, human; C000593873:Ager protein, mouse; D016229:Amyloid beta-Peptides; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D018167:Receptors, Calcitriol; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C078592:amyloid beta-protein (1-40); D002117:Calcitriol
keywords: 1,25(OH)(2)D(3); Alzheimer’s disease; LRP1; RAGE; VDR; amyloid-β(1–40)