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. Astrocytesecreted 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.

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

“…29 ApoE3, but not apoE4, effectively inhibits CypA-MMP-9 pathway in pericytes in vitro and in transgenic APOE3 mice in vivo acting through LRP1, which leads to LRP1-dependent transcriptional suppression of CypA and a subsequent transcriptional MMP-9 inhibition, as reported. 29 Compared with apoE3, apoE4 interacts weakly with LRP1 on vascular cells, 29,35 which leads to a loss of inhibition of CypA-MMP-9 pathway and its activation over time causing a progressive age-dependent BBB breakdown as shown in transgenic APOE4 mice. 29 LRP1 levels are reduced in brain capillaries in AD 35,36 that is not influenced by APOE genotype as we show in the present study by demonstrating a comparable loss of LRP1 from brain capillaries in AD APOE3 and AD APOE4 carriers.…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Data from in vitro studies support the idea that apoE facilitates the binding and internalization of soluble Ab by cells or its clearance via enzymes such as neprilysn (Beffert et al 1998;Yang et al 1999;Cole and Ard 2000;Koistinaho et al 2004;Jiang et al 2008). Although in vitro studies suggest that apoE enhances cellular Ab uptake and degradation (Kim et al 2009a), there is in vivo evidence that apoE retards Ab clearance from the brain (DeMattos et al 2004;Bell et al 2007;Deane et al 2008), possibly via an effect at the blood -brain barrier (BBB) (Fig. 1) (Zlokovic 2008).…”

“…E3 . E2) Ito et al 2007;Deane et al 2008). In addition, apoE can influence the pathogenesis of CAA in an amyloid protein precursor (APP)-transgenic mouse model, with apoE4 increasing the amount of vascular plaques in comparison to apoE3 (Fryer et al 2005b In vitro and in vivo data including data in humans and animal models suggests that the physical interaction of apoE with Ab plays an important role in AD and CAA pathogenesis (Fig.…”

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

“…APOE is a major lipid transport molecule in the central nervous system. Additionally, APOE acts as a scavenger of soluble amyloid and has been hypothesized to play a role in amyloid plaque metabolism and clearance (Beffert and Poirier, 1996;Deane et al, 2008). Very recent genome wide association studies have provided compelling evidence that genetic variations in the apolipoprotein J gene (also known as clusterin, CLU) are associated with the risk of developing Alzheimer's disease (Harold et al, 2009;Lambert et al, 2009;van Es and van den Berg, 2009) While all nucleated cells are capable of synthesizing cholesterol, the majority of cells meet their cholesterol requirements via lipoprotein mediated uptake of cholesterol.…”