Research
1α,25-Dihydroxyvitamin D3 enhances cerebral clearance of human amyloid-β peptide(1-40) from mouse brain across the blood-brain barrier
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* Corresponding author: Tetsuya Terasaki terasaki@mail.pharm.tohoku.ac.jp
1 Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
2 SORST of the Japan Science and Technology Agency, Japan
Fluids and Barriers of the CNS 2011, 8:20 doi:10.1186/2045-8118-8-20
Published: 8 July 2011Abstract
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.