1α,25-Dihydroxyvitamin D(3 )enhances cerebral clearance of human amyloid-β peptide(1-40) from mouse brain across the blood-brain barrier

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)(2)D3), an active form of vitamin D, on cerebral Aβ clearance from mouse brain. METHODS: The elimination of [(125)I]hAβ(1-40) from mouse brain was examined by using the Brain Efflux Index method to determine the remaining amount of [(125)I]hAβ(1-40) radioactivity after injection into the cerebral cortex. [(125)I]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)(2)D3 (1 μg/mouse), [(125)I]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)(2)D3, 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)(2)D3 has a VDR-mediated genomic action. Furthermore, forskolin, which activates mitogen-activated protein kinase kinase (MEK), enhanced [(125)I]hAβ(1-40) elimination from mouse brain. Forskolin also enhanced [(125)I]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)(2)D3, 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.