RT Journal Article
SR Electronic
T1 Apolipoprotein A-I crosses the blood-brain barrier through clathrin-independent and cholesterol-mediated endocytosis
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.118.254201
DO 10.1124/jpet.118.254201
A1 Andrew L Zhou
A1 Suresh K Swaminathan
A1 Geoffry L Curran
A1 Joseph F Poduslo
A1 Val J Lowe
A1 Ling Li
A1 Karunya K Kandimalla
YR 2019
UL http://jpet.aspetjournals.org/content/early/2019/04/10/jpet.118.254201.abstract
AB Recent studies suggest that apolipoprotein A-I (ApoA-I), the major protein constituent of high density lipoprotein particles, plays a critical role in preserving cerebrovascular integrity and reducing Alzheimer's risk. ApoA-I present in brain is thought to be primarily derived from the peripheral circulation. Although plasma-to-brain delivery of ApoA-I is claimed to be handled by the blood-cerebrospinal fluid barrier (BCSFB), contribution by the blood-brain barrier (BBB), which serves as a major portal for protein delivery to brain, cannot be ruled out. In this study, we assessed the permeability-surface area product (PS) of radioiodinated ApoA-I (125I-ApoA-I) in various brain regions of wild-type rats following an intravenous bolus injection. The PS value at the cortex, caudate putamen, hippocampus, thalamus, brain stem, and cerebellum was found to be 0.39, 0.28, 0.28, 0.36, 0.69, and 0.76 (mL/g/s x 10-6), respectively. Solutes delivered into brain via the BCSFB are expected to show greater accumulation in thalamus due to its periventricular location. The modest permeability for 125I-ApoA-I into thalamus relative to other regions suggests that BCSFB transport accounts for only a portion of total brain uptake and therefore BBB transport cannot be neglected. In addition, we show that Alexa Flour™ 647-labeled ApoA-I (AF647-ApoA-I) undergoes clathrin-independent and cholesterol-mediated endocytosis in transformed human cerebral microvascular endothelial cells (hCMEC/D3). Further, Z-series confocal images of the hCMEC/D3 monolayers and western blot detection of intact ApoA-I on the abluminal side demonstrated AF647-ApoA-I transcytosis across the endothelium. These findings implicate the BBB as a significant portal for ApoA-I delivery into brain.