apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain

Neurotoxic amyloid beta peptide (A beta) accumulates in the brains of individuals with Alzheimer disease (AD). The APOE4 allele is a major risk factor for sporadic AD and has been associated with increased brain parenchymal and vascular amyloid burden. How apoE isoforms influence A beta accumulation in the brain has, however, remained unclear. Here, we have shown that apoE disrupts A beta clearance across the mouse blood-brain barrier (BBB) in an isoform-specific manner (specifically, apoE4 had a greater disruptive effect than either apoE3 or apoE2). A beta binding to apoE4 redirected the rapid clearance of free A beta 40/42 from the LDL receptor-related protein 1 (LRP1) to the VLDL receptor (VLDLR), which internalized apoE4 and A beta-apoE4 complexes at the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as A beta-apoE2 and A beta-apoE3 complexes were cleared at the BBB via both VLDLR and LRP1 at a substantially faster rate than A beta-apoE4 complexes. Astrocyte-secreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their complexes with A beta were cleared at the BBB by mechanisms similar to those of their respective lipid-poor isoforms but at 2- to 3-fold slower rates. Thus, apoE isoforms differentially regulate A beta clearance from the brain, and this might contribute to the effects of APOE genotype on the disease process in both individuals with AD and animal models of AD.