Abstract
BackgroundCerebrovascular 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.MethodsThe 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).ResultsTwenty-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.ConclusionsThe 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.
Highlights
Cerebrovascular dysfunction has been considered to cause impairment of cerebral amyloid-b peptide (Ab) clearance across the blood-brain barrier (BBB)
Since clinical studies have provided evidence that vascular dysfunction plays an important role in early progression of Alzheimer’s disease (AD) [21,22,23], we hypothesized that serum vitamin D affects the function of brain capillaries, including the brain-to-blood efflux transport of Ab
Effect of 1,25(OH)2D3 on the brain-to-blood efflux transport rate of [125I]hAb(1-40) at the BBB To examine the effect of 1,25(OH)2D3 treatment on brain-to-blood [125I]hAb(1-40) efflux transport across the BBB, the time profile of the percentage of [125I]hAb
Summary
Cerebrovascular dysfunction has been considered to cause impairment of cerebral amyloid-b peptide (Ab) clearance across the blood-brain barrier (BBB). Low levels of vitamin D are associated with increased risk of Alzheimer’s disease, as well as vascular dysfunction. It has been proposed that impairment of cerebral Ab. Epidemiological studies have suggested that a low level of serum 25-hydroxyvitamin D3 (25(OH)D3), the major circulating form of vitamin D, is associated with cognitive impairment in elderly persons [10,11,12] and is a risk factor for AD [13,14]. It was reported that low levels of serum 25 (OH)D3 are associated with increased risk for cardiovascular diseases, hypertension and diabetes mellitus [17,18,19,20], which are associated with vascular dysfunction. Since clinical studies have provided evidence that vascular dysfunction plays an important role in early progression of AD [21,22,23], we hypothesized that serum vitamin D affects the function of brain capillaries, including the brain-to-blood efflux transport of Ab
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