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1?,25-Dihydroxyvitamin D3 enhances cerebral clearance of human amyloid-? peptide(1-40) from mouse brain across the blood-brain barrier.

ABSTRACT: BACKGROUND: Cerebrovascular dysfunction has been considered to cause impairment of cerebral amyloid-? peptide (A?) 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 1?,25-dihydroxyvitamin D3 (1,25(OH)2D3), an active form of vitamin D, on cerebral A? clearance from mouse brain. METHODS: The elimination of [125I]hA?(1-40) from mouse brain was examined by using the Brain Efflux Index method to determine the remaining amount of [125I]hA?(1-40) radioactivity after injection into the cerebral cortex. [125I]hA?(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 ?g/mouse), [125I]hA?(1-40) elimination from mouse brain was increased 1.3-fold, and the level of endogenous A?(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?(1-40) elimination from mouse brain. Forskolin also enhanced [125I]hA?(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 A?(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?(1-40) elimination at the BBB.

SUBMITTER: Ito S

PROVIDER: S-EPMC3162579 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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1α,25-Dihydroxyvitamin D3 enhances cerebral clearance of human amyloid-β peptide(1-40) from mouse brain across the blood-brain barrier.

Ito Shingo S Ohtsuki Sumio S Nezu Yasuko Y Koitabashi Yusuke Y Murata Sho S Terasaki Tetsuya T

Fluids and barriers of the CNS 20110708

<h4>Background</h4>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.<h4>Methods</h4>The elimina ...[more]

PMID: 21740543

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Project description:Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking.An open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH)2D3 in vitamin D-insufficient patients with CKD (n=15) and controls with normal kidney function (n=15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters.Vitamin D3 and 25(OH)D3 concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D3 change, 8.6 ng/ml [interquartile range, 3.9-25.6 ng/ml] for controls versus 12.6 ng/ml [6.9-41.2 ng/ml] for CKD [P=0.15]; 25(OH)D3 change, 39.2 ng/ml [30.9-47.2 ng/ml] for controls versus 39.9 ng/ml [31.5-44.1 ng/ml] for CKD [P=0.58]). Likewise, the absolute increase in 1?,25(OH)2D3 was similar between CKD participants and controls (change, 111.2 pg/ml [64.3-141.6 pg/ml] for controls versus 101.1 pg/ml [74.2-123.1 pg/ml] for CKD; P=0.38). Baseline and post-treatment 24,25(OH)2D3 concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)2D3 after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3-3.5 ng/ml] for controls versus 1.2 ng/ml [0.6-1.9 ng/ml] for patients with CKD; P<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)2D3 for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis.Patients with CKD exhibit an altered ability to increase serum 24,25(OH)2D3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH)2D3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.

Dataset Information

1?,25-Dihydroxyvitamin D3 enhances cerebral clearance of human amyloid-? peptide(1-40) from mouse brain across the blood-brain barrier.

Publications

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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