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 (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.
CONCLUSION: 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.