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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>The 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).</p> <p>Results</p> <p>Twenty-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.</p> <p>Conclusions</p> <p>The 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.</p

Status of adult outpatients with congenital heart disease in Japan: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease Registry

BackgroundThe Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease (JNCVD-ACHD) was founded in 2011 for the lifelong care of adult patients with congenital heart disease (ACHD patients). This network maintains the first Japanese ACHD registry.Methods and resultsFrom 2011 to 2019, the JNCVD-ACHD registered 54 institutions providing specialized care for ACHD patients in 32 of the 47 prefectures in Japan. The registry collected data on the disease profile for 24,048 patients from 50 institutions and the patient characteristics for 9743 patients from 24 institutions. The most common ACHDs were atrial septal defect (20.5 %), ventricular septal defect (20.5 %), tetralogy of Fallot (12.9 %), and univentricular heart (UVH)/single ventricle (SV; 6.6 %). ACHD patients without biventricular repair accounted for 37.0 % of the population. Also examined were the serious anatomical and/or pathophysiological disorders such as pulmonary arterial hypertension (3.0 %) including Eisenmenger syndrome (1.2 %), systemic right ventricle under biventricular circulation (sRV-2VC; 2.8 %), and Fontan physiology (6.0 %). The sRV-2VC cases comprised congenitally corrected transposition of the great arteries without anatomical repair (61.9 %) and transposition of the great arteries with atrial switching surgery (38.1 %). The primary etiology (86.4 %) for Fontan physiology was UVH/SV. In addition, developmental/chromosomal/genetic disorders were heterotaxy syndromes (asplenia, 0.9 %; polysplenia, 0.7 %), trisomy 21 (4.0 %), 22q11.2 deletion (0.9 %), Turner syndrome (0.2 %), and Marfan syndrome (1.1 %).ConclusionsAlthough the specific management of ACHD has systematically progressed in Japan, this approach is still evolving. For ideal ACHD care, the prospective goals for the JNCVD-ACHD are to create local networks and provide a resource for multicenter clinical trials to support evidence-based practice

Atrial natriuretic peptide is eliminated from the brain by natriuretic peptide receptor-C-mediated brain-to-blood efflux transport at the blood–brain barrier

Cerebral atrial natriuretic peptide (ANP), which is generated in the brain, has functions in the regulation of brain water and electrolyte balance, blood pressure and local cerebral blood flow, as well as in neuroendocrine functions. However, cerebral ANP clearance is still poorly understood. The purpose of this study was to clarify the mechanism of blood–brain barrier (BBB) efflux transport of ANP in mouse. Western blot analysis showed expression of natriuretic peptide receptor (Npr)-A and Npr-C in mouse brain capillaries. The brain efflux index (BEI) method confirmed elimination of [125I]human ANP (hANP) from mouse brain across the BBB. Inhibition studies suggested the involvement of Npr-C in vivo. Furthermore, rapid internalization of [125I]hANP by TM-BBB4 cells (an in vitro BBB model) was significantly inhibited by Npr-C inhibitors and by two different Npr-C-targeted short interfering RNAs (siRNAs). Finally, treatment with 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) significantly increased Npr-C expression in TM-BBB4 cells, as determined by liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based targeted absolute proteomics. Our results indicate that Npr-C mediates brain-to-blood efflux transport of ANP at the mouse BBB as a pathway of cerebral ANP clearance. It seems likely that levels of natriuretic peptides in the brain are modulated by 1,25(OH)2D3 through upregulation of Npr-C expression at the BBB