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

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.

Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study

“…Vitamin D also has a role in buffering antioxidant defenses [1, 44], stimulating neurotrophin release [47], and downregulating calcium channel expression [48, 49]. Vitamin D may attenuate amyloid-β (A β) accumulation by stimulating the phagocytosis of the Aβ peptide [50] and by enhancing brain-to-blood Aβ efflux transport at the blood-brain barrier [51], with a decreased number of amyloid plaques as a result [52]. Conversely, vitamin D receptor knock-out mice manifest behavioral abnormalities [41], and reduced concentrations of the vitamin D hormone receptor mRNA have been directly linked with AD [53].…”

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

“…In post-mortem AD brain, a decreased level of VDR mRNA has been reported in hippocampal region [184]. 1, 25 dihydroxy vitamin D has been shown to increase the clearance of Aβ peptide from mouse brain [185]. In neuroblastoma cells, VDR overexpression or vitamin D treatment increases APP transcription [177].…”

Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1

“…Following the discovery of the vitamin D receptor (VDR), which is expressed in a wide range of tissues, the role of vitamin D in the prevention and treatment of chronic diseases has become an important area of study (Holick, 1992; Kalueff and Tuohimaa, 2007). Vitamin D deficiency has been linked to various health problems, including cognitive decline, depression, cardiovascular disease, hypertension, type 2 diabetes, and cancer (Butler et al, 2011; Chan, 2011; Holick, 2003; Ingraham et al, 2008; Ito et al, 2011; Liu et al, 2013). During aging, the risk for vitamin D deficiency significantly increases due to reduced nutritional intake of vitamin D, increased adiposity, and decreased cutaneous synthesis of vitamin D. This has led to considerable debate regarding vitamin D supplementation in the elderly and whether deficiencies in vitamin D represent an indicator of ill-health or increases one’s susceptibility to chronic disease (Kupferschmidt, 2012).…”