apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
Rashid Deane, … , David M. Holtzman, Berislav V. Zlokovic
Rashid Deane, … , David M. Holtzman, Berislav V. Zlokovic
Published November 13, 2008
Citation Information: J Clin Invest. 2008;118(12):4002-4013. https://doi.org/10.1172/JCI36663.
View: Text | PDF
Research Article Neuroscience

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

Abstract

Neurotoxic amyloid β peptide (Aβ) 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 Aβ accumulation in the brain has, however, remained unclear. Here, we have shown that apoE disrupts Aβ 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). Aβ binding to apoE4 redirected the rapid clearance of free Aβ40/42 from the LDL receptor–related protein 1 (LRP1) to the VLDL receptor (VLDLR), which internalized apoE4 and Aβ-apoE4 complexes at the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as Aβ-apoE2 and Aβ-apoE3 complexes were cleared at the BBB via both VLDLR and LRP1 at a substantially faster rate than Aβ-apoE4 complexes. Astrocyte-secreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their complexes with Aβ 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 Aβ 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.

Authors

Rashid Deane, Abhay Sagare, Katie Hamm, Margaret Parisi, Steven Lane, Mary Beth Finn, David M. Holtzman, Berislav V. Zlokovic

×

Figure 1

apoE isoform–specific clearance across the mouse BBB in vivo.

Options: View larger image (or click on image) Download as PowerPoint
apoE isoform–specific clearance across the mouse BBB in vivo. (A) Time-d...
(A) Time-disappearance curves of 14C-inulin (reference molecule, black) and 125I-labeled human lipid-poor apoE4 (dark green), apoE3 (light green), apoE2 (yellow green), Aβ42 (dark blue), and Aβ40 (light blue) after microinfusion of tracers mixture into brain ISF in the caudate nucleus. Test tracers were studied at 40 nM. The percentage recovery in brain was calculated using Equation 1 (see Methods). TCA-precipitable 125I-radioactivity was used. Each point represents a single experiment. (B) Time-dependent efflux across the BBB of 125I-labeled Aβ40, Aβ42, lipid-poor apoE2, apoE3, and apoE4 (yellow green, light green, dark green) and lipo-apoE2 (brown), lipo-apoE3 (red), and lipo-apoE4 (orange) was calculated from data in Figure 1A and Equation 4 (see Methods). The ISF bulk flow for studied test tracers was calculated using Equation 2 (see Methods). (C) Relative contributions of transport across the BBB (black bars), ISF flow (white bars), and degradation (dark gray bars) to clearance of apoE isoforms from brain and their retention in the brain (light gray bars) were studied at 40 nM concentrations and calculated from fractional coefficients given in Supplemental Table 1. Mean ± SEM; n = 11–24 mice per group for multiple-time series. *P < 0.05, lipid-poor apoE4 versus lipid-poor apoE3 or apoE2; †P < 0.05, lipo-apoE4, lipo-apoE3, and lipo-apoE2 versus corresponding lipid-poor apoE4, apoE2 and apoE3. ‡P < 0.05, lipo-apoE4 versus lipo-apoE3 or lipo-apoE2. (D and E) Time-appearance curves of 14C-inulin and 125I-labeled lipid-poor apoE4, apoE3, and apoE2 (TCA-precipitable 125I-radioactivity) in the CSF (D) and plasma (E) from experiments as inA. ID, injected dose. §P < 0.05, apoE2, apoE3, and apoE4 versus inulin; P < 0.05, apoE4 versus apoE2 or apoE3. Mean ± SEM; n = 3–5 mice per group.