1α,25-Dihydroxyvitamin D 3enhances 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 D 3(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. © 2011 Ito et al; licensee BioMed Central Ltd.