Lipidation of apolipoprotein E influences its isoform-specific interactionwith Alzheimer's amyloid beta peptides

The inheritance of the apolipoprotein E (apoE) epsilon 4 allele is a prevai ling risk factor for sporadic and familial Alzheimer's disease (AD). ApoE i soforms bind directly to Alzheimer's amyloid beta (A beta) peptides both in vitro and in vivo. Recent studies suggest that association of apoE with li pids may modulate its interaction with A beta. We examined the binding of l ipid-associated and delipidated apoE3 and apoE4 isoforms to A beta utilizin g a solid-phase binding assay and estimated the dissociation constants for the interaction of various apoE and A beta species. Using native apoE isofo rms from stably transfected RAW 264 and human embryonic kidney 293 cells, a poE3 had greater affinity than apoE4 for both A beta 1-40 and A beta 1-42. Delipidation of apoE decreased its affinity for A beta peptides by 5-10-fol d and abolished the isoform-specificity. Conversely, incorporation of apoE iso-forms produced by baculovirus-infected Sf9 cells into reconstituted hum an high-density-lipoprotein lipoparticles restored the affinity values for A beta peptides and resulted in preferential binding of apoE3. The data dem onstrate that native lipid-associated apoE3 binds to A beta peptides with 2 -3-fold higher affinity than lipid-associated apoE4. Since the isoforms' bi nding efficiency correlate inversely with the risk of developing late-onset AD, the results suggest a possible involvement of apoE3 in the clearance o r routing out of A beta from the central nervous system as one of the mecha nisms underlying the pathology of the disease.