Apolipoprotein E, Receptors, and Modulation of Alzheimer's Disease

Abstract

Apolipoprotein E (apoE) is a lipid carrier in both the peripheral and the central nervous systems. Lipid-loaded apoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and injury repair in the brain. Considering prevalence and relative risk magnitude, the ε4 allele of the APOE gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 contributes to AD pathogenesis by modulating multiple pathways, including but not limited to the metabolism, aggregation, and toxicity of amyloid-β peptide, tauopathy, synaptic plasticity, lipid transport, glucose metabolism, mitochondrial function, vascular integrity, and neuroinflammation. Emerging knowledge on apoE-related pathways in the pathophysiology of AD presents new opportunities for AD therapy. We describe the biochemical and biological features of apoE and apoE receptors in the central nervous system. We also discuss the evidence and mechanisms addressing differential effects of apoE isoforms and the role of apoE receptors in AD pathogenesis, with a particular emphasis on the clinical and preclinical studies related to amyloid-β pathology. Finally, we summarize the current strategies of AD therapy targeting apoE, and postulate that effective strategies require an apoE isoform-specific approach.

Keywords: Alzheimer’s disease; Amyloid-β; Apolipoprotein E; Low-density lipoprotein receptor family; Synaptic plasticity; Tauopathy.

Figure 1. Schematic illustration of the structure of human apoE

ApoE can be subdivided into two major domains (–8). The amino-terminal domain includes the receptor-binding region (residues 136–150), which is responsible for the interaction of apoE and its receptors. The carboxyl-terminal domain contains the major lipid-binding region (residues 244–272), which is responsible for lipid binding. The middle region of apoE (residues 167–206) is a hinge region that joins the two domains together. The apoE2, apoE3, and apoE4 isoforms differ from one another at amino acid residues 112 and/or 158 (11). ApoE2 has Cys at both positions, apoE3 has Cys at position 112 and Arg at position 158, and apoE4 has Arg residues at both positions. The V236E variance just outside the lipid-binding region, which reduces the risk of late-onset of Alzheimer’s disease (LOAD) (122), is marked.

Figure 2. Major Aβ clearance pathways and the roles of apoE and apoE receptors

Aβ is predominantly produced by neurons (–8). The accumulation of soluble Aβ in the brain parenchyma leads to the formation of Aβ oligomers and amyloid plaques, whereas its accumulation in the perivascular region leads to CAA (–8). Soluble Aβ can be removed from the brain by various clearance pathways closely linked to each other: soluble Aβ in ISF can be cleared in brain parenchyma, transported to the blood through BBB, or is degraded by vascular mural cells. Aβ can also traffic along the ISF bulk flow into CSF sink where it could be absorbed into the circulatory and lymphatic systems (6, 60). Major Aβ clearance pathways include receptor-mediated clearance (e.g., LRP1, LDLR) by cells in the brain parenchyma (neurons and glia), uptake from the perivascular space by vascular mural cells, or proteolytic degradation by endopeptidases (e.g., NEP, IDE) (–8). Binding of Aβ to neuronal HSPGs on the cell surface hinders proteolytic degradation of Aβ, and promotes Aβ oligomerization and aggregation (75). ApoE is generated mainly by the glial cells and lipidated by ABCA1 and ABCG1 transporters, forming lipoprotein particles (15). Lipidated apoE could either bind to Aβ and facilitates Aβ clearance through cell-surface receptors (e.g., LRP1, LDLR) (apoE2 > apoE3 > apoE4) (–80). Alternatively, apoE might also suppress Aβ clearance by competing with Aβ for receptor binding in astrocytes (apoE4 > apoE3) (81). Abbreviations: Aβ, amyloid-β; BBB, blood-brain barrier; BCSFB, blood-CSF barrier; CSF, cerebrospinal fluid; ISF, interstitial fluid; CAA, cerebral amyloid angiopathy; NEP, neprilysin; IDE, insulin-degrading enzyme; LRP1, low-density lipoprotein receptor-related protein 1; LDLR, low-density lipoprotein receptor; HSPG, heparan sulfate proteoglycan; ABCA1, ATP-binding cassette A1; ABCG1, ATP-binding cassette G1.

Figure 3. ApoE-targeting strategies for treatment of Alzheimer’s disease

ApoE is primarily synthesized by astrocytes, and is lipidated by the ABCA1 transporter, forming apoE lipoprotein particles. Lipidated apoE binds soluble Aβ and facilitates Aβ uptake through cell surface receptors including LRP1, LDLR, VLDLR, and HSPG (6). ApoE and apoE receptors play critical roles in both Aβ-dependent and Aβ-independent AD pathogenic pathways (8). ApoE-directed approaches that are currently explored are categorized as below: 1) Modulating apoE level, stability and lipidation (ie., LXR/RXR agonists (–105, 108), apoE stabilizing compounds (111), nanoparticles or AAV-mediated gene delivery of apoE (40, 113), gene silencing approaches and anti-apoE immunotherapy (115, 116); 2) Modulating apoE properties by converting apoE4 to apoE3 (i.e., structure correctors, CRISPR/Cas9 genome-editing) (–121), suppressing apoE aggregation (122) and proteolysis (118, 119) and blocking apoE-Aβ interaction (126, 127); 3) Regulating the levels, intracellular trafficking and functions of apoE and apoE receptors (6, 72, 75, 98); 4) Restoring normal apoE functions (i.e., apoE-mimetic peptides) (128); 5) Restoring apoE4-mediated defects by apoE2-based treatment (40, 113), and 6) Promoting cerebrovascular functions (i.e., physical exercise, healthy diet and lifestyle), particularly in APOE4 carriers (142). Abbreviations: Aβ, amyloid-β; apoE, apolipoprotein E; LXR, liver X receptor; RXR, retinoid X receptor; ABCA1, ATP-binding cassette A1; HSPG, heparan sulphate proteoglycan; LDLR, low-density lipoprotein receptor; LRP1, low-density lipoprotein receptor-related protein 1; BBB, blood-brain barrier; ApoER2, apolipoprotein E receptor 2; AAV, adeno-associated virus.