A Multifaceted Role for apoE in the Clearance of Beta-Amyloid across the Blood-Brain Barrier

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 (A beta) removal from the brain, is not clearly defined. Objective: To elucidate the influence of apoE on the clearance of A beta across the blood-brain barrier (BBB). Methods: A beta (1-42) was intra-cerebrally 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 A beta (1-42) appearing in the plasma than wild-type or apoE knockout mice, indicating an enhanced clearance of A beta from the brain to the periphery. In vitro, unbound basolateral apoE3 (i.e., not bound to A beta), and to a lesser extent unbound apoE4, at concentrations <= 10 nM facilitated basolateral-to-apical fluorescein-A beta (1-42) transcytosis across a BBB model, while apoE isoforms bound to A beta significantly disrupted A beta transcytosis. Additionally, following apical exposure to the BBB model, we found that apoE4 bound to A beta is able to penetrate the BBB more readily than apoE3 bound to A beta and does so via the RAGE (receptor for advanced glycation end products) transporter. Conclusion: These studies indicate a multifaceted, isoform-dependent role for apoE in the exchange of A beta across the BBB and may partially explain the association of apoE4 and A beta brain accumulation in AD. Copyright (C) 2012 S. Karger AG, Basel