%0 Journal Article
%T 1¦Á,25-Dihydroxyvitamin D3 enhances cerebral clearance of human amyloid-¦Â peptide(1-40) from mouse brain across the blood-brain barrier
%A Shingo Ito
%A Sumio Ohtsuki
%A Yasuko Nezu
%A Yusuke Koitabashi
%A Sho Murata
%A Tetsuya Terasaki
%J Fluids and Barriers of the CNS
%D 2011
%I BioMed Central
%R 10.1186/2045-8118-8-20
%X The elimination of [125I]hA¦Â(1-40) from mouse brain was examined by using the Brain Efflux Index method to determine the remaining amount of [125I]hA¦Â(1-40) radioactivity after injection into the cerebral cortex. [125I]hA¦Â(1-40) internalization was analyzed using conditionally immortalized mouse brain capillary endothelial cells (TM-BBB4).Twenty-four hours after intraperitoneal injection of 1,25(OH)2D3 (1 ¦Ìg/mouse), [125I]hA¦Â(1-40) elimination from mouse brain was increased 1.3-fold, and the level of endogenous A¦Â(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]hA¦Â(1-40) elimination from mouse brain. Forskolin also enhanced [125I]hA¦Â(1-40) internalization in TM-BBB4 cells, and this enhancement was inhibited by a MEK inhibitor, suggesting involvement of non-genomic action.The active form of vitamin D, 1,25(OH)2D3, appears to enhance brain-to-blood A¦Â(1-40) efflux transport at the BBB through both genomic and non-genomic actions. Compounds activating these pathways may be candidate agents for modulating A¦Â(1-40) elimination at the BBB.An abnormally elevated level of amyloid-¦Â peptide (A¦Â) in the brain is one of the prominent features of Alzheimer's disease (AD) [1]. A¦Â is normally produced by neurons and cleared through degradation by proteinases within the brain [2-4], as well as through elimination from the brain to the circulating blood via an efflux transport system at the blood-brain barrier (BBB) [5,6]. It has been proposed that impairment of cerebral A¦Â clearance leads to abnormally elevated brain A¦Â levels in late-onset AD which accounts for more than 90% of all cases of AD. On the other hand, somatostatin was repor
%U http://www.fluidsbarrierscns.com/content/8/1/20