Intravenously injected human apolipoprotein A-I rapidly enters the central nervous system via the choroid plexus

J Am Heart Assoc. 2014 Nov 12;3(6):e001156. doi: 10.1161/JAHA.114.001156.

Abstract

Background: Brain lipoprotein metabolism is dependent on lipoprotein particles that resemble plasma high-density lipoproteins but that contain apolipoprotein (apo) E rather than apoA-I as their primary protein component. Astrocytes and microglia secrete apoE but not apoA-I; however, apoA-I is detectable in both cerebrospinal fluid and brain tissue lysates. The route by which plasma apoA-I enters the central nervous system is unknown.

Methods and results: Steady-state levels of murine apoA-I in cerebrospinal fluid and interstitial fluid are 0.664 and 0.120 μg/mL, respectively, whereas brain tissue apoA-I is ≈10% to 15% of its levels in liver. Recombinant, fluorescently tagged human apoA-I injected intravenously into mice localizes to the choroid plexus within 30 minutes and accumulates in a saturable, dose-dependent manner in the brain. Recombinant, fluorescently tagged human apoA-I accumulates in the brain for 2 hours, after which it is eliminated with a half-life of 10.3 hours. In vitro, human apoA-I is specifically bound, internalized, and transported across confluent monolayers of primary human choroid plexus epithelial cells and brain microvascular endothelial cells.

Conclusions: Following intravenous injection, recombinant human apoA-I rapidly localizes predominantly to the choroid plexus. Because apoA-I mRNA is undetectable in murine brain, our results suggest that plasma apoA-I, which is secreted from the liver and intestine, gains access to the central nervous system primarily by crossing the blood-cerebrospinal fluid barrier via specific cellular mediated transport, although transport across the blood-brain barrier may also contribute to a lesser extent.

Keywords: ApoA‐I; central nervous system; cerebrovascular endothelium; choroid plexus; transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoprotein A-I / administration & dosage*
  • Apolipoprotein A-I / blood
  • Apolipoprotein A-I / cerebrospinal fluid
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / pharmacokinetics*
  • Biological Transport
  • Blood-Brain Barrier / metabolism*
  • Capillary Permeability
  • Cells, Cultured
  • Choroid Plexus / metabolism*
  • Endothelial Cells / metabolism
  • Epithelial Cells / metabolism
  • Female
  • Half-Life
  • Humans
  • Injections, Intravenous
  • Metabolic Clearance Rate
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacokinetics
  • Tissue Distribution

Substances

  • APOA1 protein, human
  • Apolipoprotein A-I
  • Recombinant Proteins