The low-density lipoprotein (LDL) receptor gene family. (A) The core LDL receptor gene family as it exists in mammalian species. These family members are characterized by one or more ligand-binding domains, epidermal growth factor (EGF), homology domains consisting of EGF repeats and YWTD propeller (β-propeller) domains involved in pH-dependent release of ligands in the endosomes, a single transmembrane domain and a cytoplasmic tail containing at least one NPxY motif. The latter represents both the endocytosis signal as well as a binding site for adaptor proteins linking the receptor to intracellular signaling pathways. Furthermore, LDLR, VLDLR, and Apoer2 carry an O-linked sugar domain. (B) Equivalent receptors that are structurally and functionally distinct family members in nonmammalian species. (C) A subgroup of functionally important, but more distantly related family members that share some, but not all, of the structural requirements of the “core members.” In addition, they could also contain domains, e.g., vacuolar protein sorting (VPS) domains, which are not present in the core family. (From Dieckmann et al. 2010; reprinted, with permission, from Walter de Gruyter GmbH © 2010.)

Pathways by which apoE and Aβ interact in the brain. ApoE is primarily produced by both astrocytes and microglia and is subsequently lipidated by ABCA1 to form lipoprotein particles. In the extracellular space, lipidated apoE binds to soluble Aβ in an isoform-dependent pattern (E2 > E3 > E4) and influences the formation of parenchymal amyloid plaques and transport of Aβ within the CNS. ApoE is endocytosed into various cell types within the brain by different members of the LDL receptor family, including LDLR and LRP1. ApoE may also facilitate the cellular uptake of Aβ through the endocytosis of a complex of apoE-containing lipoprotein particles bound to Aβ in a manner that likely depends on the isoforms and its level of lipidation. Furthermore, apoE has been shown to directly enhance both the degradation of Aβ within microglial cells and the ability of astrocytes to clear diffuse Aβ deposits (Koistinaho et al. 2004; Jiang et al. 2008). Aβ associated with apoE-containing lipoprotein particles may also be retained within the CNS through their binding to heparin sulfate proteoglycan (HSPG) moieties present in the extracellular space (Mahley and Rall 2000). At the blood–brain barrier (BBB), soluble Aβ is predominantly transported from the interstitial fluid into the bloodstream via LRP1 and P-glycoprotein (Cirrito et al. 2005; Zlokovic 2008). ApoE has been shown to slow the transport of Aβ across the BBB in an isoform-dependent manner (E4 > E3 > E2) (Bell et al. 2007; 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). (From Kim et al. 2009; reprinted, with permission, from Elsevier © 2009.)

ApoE isoforms differentially impair ApoE receptor and glutamate receptor recycling at the synapse. Apoer2 induces N-methyl-d-aspartate receptor (NMDAR) tyrosine phosphorylation by activating Src family tyrosine kinases (SFKs) in response to Reelin in the postsynaptic neuron. Astrocyte-derived ApoE3 (green ovals) or ApoE4 (gray ovals) bind to Apoer2 and are constitutively but slowly internalized. Apoer2 undergoes accelerated endocytosis in response to Reelin signaling. ApoE4 sequesters Apoer2 in intracellular compartments along with glutamate receptors (NMDAR and GluR), thereby reducing the ability of the postsynaptic neuron to recycle these proteins with normal kinetics, whereas ApoE2 or ApoE3 efficiently recycle back to the cell surface and thus deplete surface Apoer2 and glutamate receptor levels to a lesser extent (illustrated on the left for ApoE3). Aβ oligomers interfere with NMDAR tyrosine phosphorylation by activating tyrosine phosphatases (Snyder et al. 2005). (Modified from Chen et al. 2010; reprinted, with permission, from the National Academy of Sciences © 2010.)

Schematic model of LRP1/LDLR-mediated cellular transport of apoE/lipoprotein and Aβ. Three cell-surface receptors, LRP1, LDLR, and HSPG, are capable of binding to apoE/lipoprotein, Aβ, and apoE/lipoprotein/Aβ complexes. On clathrin-mediated endocytosis, ligands are mostly dissociated from the receptors within the early/sorting endosomes owing to lower pH. Whereas receptors are typically recycled back to the cell surface, ligands are delivered to multivesicular bodies (MVBs)/late endosomes and eventually to lysosomes for degradation. Lipid components are transported out of the lysosomes for storage or reutilization. Depending on the concentrations and cellular conditions, some Aβ molecules might aggregate within the lysosomes as intracellular Aβ, which could eventually serve to seed amyloid plaques (Hu et al. 2009).