title: 1α,25-Dihydroxyvitamin D3 enhances cerebral clearance of human amyloid-β peptide(1-40) from mouse brain across the blood-brain barrier.
abstract: BACKGROUND
  Cerebrovascular dysfunction has been considered to cause impairment of cerebral amyloid-β peptide (Aβ) clearance across the blood-brain barrier (BBB). Further, low levels of vitamin D are associated with increased risk of Alzheimer's disease, as well as vascular dysfunction. The purpose of the present study was to investigate the effect of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), an active form of vitamin D, on cerebral Aβ clearance from mouse brain.
  
  
  METHODS
  The elimination of [125I]hAβ(1-40) from mouse brain was examined by using the Brain Efflux Index method to determine the remaining amount of [125I]hAβ(1-40) radioactivity after injection into the cerebral cortex. [125I]hAβ(1-40) internalization was analyzed using conditionally immortalized mouse brain capillary endothelial cells (TM-BBB4).
  
  
  RESULTS
  Twenty-four hours after intraperitoneal injection of 1,25(OH)2D3 (1 μg/mouse), [125I]hAβ(1-40) elimination from mouse brain was increased 1.3-fold, and the level of endogenous Aβ(1-40) in mouse brain was reduced. These effects were observed at 24 h after i.p. injection of 1,25(OH)2D3, while no significant effect was observed at 48 or 72 h. Vitamin D receptor (VDR) mRNA was detected in mouse brain capillaries, suggesting that 1,25(OH)2D3 has a VDR-mediated genomic action. Furthermore, forskolin, which activates mitogen-activated protein kinase kinase (MEK), enhanced [125I]hAβ(1-40) elimination from mouse brain. Forskolin also enhanced [125I]hAβ(1-40) internalization in TM-BBB4 cells, and this enhancement was inhibited by a MEK inhibitor, suggesting involvement of non-genomic action.
  
  
  CONCLUSIONS
  The active form of vitamin D, 1,25(OH)2D3, appears to enhance brain-to-blood Aβ(1-40) efflux transport at the BBB through both genomic and non-genomic actions. Compounds activating these pathways may be candidate agents for modulating Aβ(1-40) elimination at the BBB.
authors: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. terasaki@mail.pharm.tohoku.ac.jp.
authors: Shingo
authors: S
authors: Ito
authors: Sumio
authors: S
authors: Ohtsuki
authors: Yasuko
authors: Y
authors: Nezu
authors: Yusuke
authors: Y
authors: Koitabashi
authors: Sho
authors: S
authors: Murata
authors: Tetsuya
authors: T
authors: Terasaki