title: A multifaceted role for apoE in the clearance of beta-amyloid across the blood-brain barrier.
abstract: BACKGROUND
  While apolipoprotein E4 (apoE4) is highly correlated with the development of Alzheimer's disease (AD), its role in AD pathology and, in particular, beta-amyloid (Aβ) removal from the brain, is not clearly defined.
  
  
  OBJECTIVE
  To elucidate the influence of apoE on the clearance of Aβ across the blood-brain barrier (BBB).
  
  
  METHODS
  Aβ(1-42) was intracerebrally administered to transgenic mice expressing human apoE isoforms and examined in the periphery.
  
  
  RESULTS
  apoE3 and apoE4 mice had 5 times and 2 times, respectively, more Aβ(1-42) appearing in the plasma than wild-type or apoE knockout mice, indicating an enhanced clearance of Aβ from the brain to the periphery. In vitro, unbound basolateral apoE3 (i.e., not bound to Aβ), and to a lesser extent unbound apoE4, at concentrations ≤10 nM facilitated basolateral-to-apical fluorescein-Aβ(1-42) transcytosis across a BBB model, while apoE isoforms bound to Aβ significantly disrupted Aβ transcytosis. Additionally, following apical exposure to the BBB model, we found that apoE4 bound to Aβ is able to penetrate the BBB more readily than apoE3 bound to Aβ and does so via the RAGE (receptor for advanced glycation end products) transporter.
  
  
  CONCLUSIONS
  These studies indicate a multifaceted, isoform-dependent role for apoE in the exchange of Aβ across the BBB and may partially explain the association of apoE4 and Aβ brain accumulation in AD.
authors.affiliation: The Roskamp Institute, Sarasota, FL 34243, USA. cbachmeier@rfdn.org
authors.forename: Corbin
authors.initials: C
authors.lastname: Bachmeier
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
authors.forename: David
authors.initials: D
authors.lastname: Beaulieu-Abdelahad
authors.forename: Benoit
authors.initials: B
authors.lastname: Mouzon
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology; D002478:Cells, Cultured; D042783:Endothelial Cells; D005353:Fibronectins / Q000008:administration & dosage; D007839:Functional Laterality; D024243:HMGB1 Protein / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000166:cytology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D057900:Transcytosis / Q000187:drug effects / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D005353:Fibronectins; D024243:HMGB1 Protein; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)