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.
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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

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Figure 3

apoE isoforms disrupt Aβ clearance across the mouse BBB in vivo (apoE4>apoE3 or apoE2) by redirecting differentially redirecting transport of Aβ-apoE complexes from LRP1 to VLDLR.

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apoE isoforms disrupt Aβ clearance across the mouse BBB in vivo (apoE4&g...
125I-labeled apoE-Aβ complexes (40 nM) and 14C-inulin were microinfused into brain ISF and clearance determined at 90 minutes. 125I-label was either on Aβ40 and Aβ42 or on apoE2 and apoE4. (A) FPLC purification of apoE2-Aβ40. Upper panel shows dot blots of Aβ40-apoE2 and free Aβ peaks with Aβ-specific (6E10) and apoE-specific (3D12) antibodies. (B and C) BBB clearance of Aβ40 (B) and Aβ42 (C) with and without an LRP1-specific blocking antibody and of their complexes with lipid-poor and lipo-apoE2 and lipid-poor and lipo-apoE4, as indicated. (D) Clearance of Aβ40 and Aβ42 by transport across the BBB (black bars), ISF flow (white bars) and degradation (light gray bars) and retention in the brain (dark gray bars) studied from different 125I-Aβ40-apoE and Aβ42-apoE complexes at 40 nM and compared with free Aβ40 or Aβ42. 125I-label was on Aβ. Clearance and retention were calculated from fractional coefficients using Equations 2, 5, and 6 (see Methods). Mean ± SEM, n = 5–6 mice per group in a single time-point series. *P < 0.05, Aβ40-apoE2 and Aβ40-apoE4 versus Aβ40 and Aβ42–lipo-apoE2, Aβ42–lipo-apoE3, and Aβ42–lipo-apoE4 versus Aβ42; †P < 0.05, Aβ40-apoE4 versus Aβ40-apoE2 and Aβ42–lipo-apoE4 versus Aβ42–lipo-apoE3 or Aβ42–lipo-apoE2; ‡P < 0.05, Aβ40–lipo-apoE2 and Aβ40–lipo-apoE4 versus Aβ40-apoE2 and Aβ40-apoE4; §P < 0.05, Aβ40–lipo-apoE4 versus Aβ40–lipo-apoE3 or Aβ40–lipo-apoE2. (E) BBB clearance of 125I-Aβ40–lipo-apoE2 and 125I-Aβ40–lipo-apoE3 in control mice with and without blocking antibodies to VLDLR, LRP1, and LDLR. (F and G) BBB clearance of 125I-Aβ40–lipo-apoE2 (F) and 125I-Aβ42–lipo-apoE4 complexes (G) in control (white bars), VLDLR–/– (gray bars), and RAP–/– (black bars) mice with and without blocking antibodies to LRP1, VLDLR, and/or LDLR. Mean ± SEM; n = 4–6 mice per group.