APOE and Alzheimer's Disease: From Lipid Transport to Physiopathology and Therapeutics

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by extracellular amyloid β (Aβ) and intraneuronal tau protein aggregations. One risk factor for developing AD is the APOE gene coding for the apolipoprotein E protein (apoE). Humans have three versions of APOE gene: ε2, ε3, and ε4 allele. Carrying the ε4 allele is an AD risk factor while carrying the ε2 allele is protective. ApoE is a component of lipoprotein particles in the plasma at the periphery, as well as in the cerebrospinal fluid (CSF) and in the interstitial fluid (ISF) of brain parenchyma in the central nervous system (CNS). ApoE is a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the CNS, and that regulates multiple important signaling pathways. This review will focus on the critical role of apoE in AD pathogenesis and some of the currently apoE-based therapeutics developed in the treatment of AD.

Keywords: APOE; APOE receptors; Alzheimer’s disease; amyloid β; lipidation; therapeutics.

FIGURE 1

Global distribution of APOE4 allele in Homo sapiens. Frequency of ε4 is low (light red regions) and high (dark red regions). The gray color indicates that there are no data available for this country. The geographical map of APOE4 frequency was generated using the package, rworldmapR. State estimates were generated by averaging the frequency of APOE4 allele across the various studies conducted in a specific country.

FIGURE 2

Schematic illustration of structural and functional regions of apoE protein. (A) Location and structure of the APOE gene on chromosome 19 at position q13.32. The APOE gene has 4 exons, respectively consisting of 44, 66, 193, and 860 nucleotides, with exon 4 coding for over 80% of the protein. Exon 1 contains the 5′ untranslated region (5′UTR). The wild-type sequence is apoE3 (Cys112, Arg158). Point mutations in the exon 4 generate two single nucleotide polymorphisms (SNPs): a T → C point mutation produces apoE4 (C112R), while C → T mutation gives apoE2 (R158C). (B) Diagram of human apoE structural domains. The N-terminal region contains the receptor-binding site (residues 134–150) and four helices (1–4), the C-terminal region contains the lipid-binding region (residues 244–272) and the two domains are joined by a hinge region. The N-terminal region contains the two polymorphic positions (112 and 158) that discriminate the three apoE isoforms. The lower part of the figure shows the α-helical segment (residues 134–150) that recognizes the LDL receptor. This segment is rich in positively charged arginine and lysine residues.

FIGURE 3

Schematic overview of Aβ-independent roles for apoE in Alzheimer’s disease pathology. The isoform-dependent effects of APOE are indicated. Abbreviations: apoE, apolipoprotein E; NFT, neurofibrillary tangle; BBB, blood brain barrier; IL, interleukin; TNF-α, Tumor necrosis factor-α; ROS, reactive oxygen species.

FIGURE 4

ApoE isoform-dependent effects on Aβ metabolism and clearance. Aβ is mainly produced by neurons via proteolytic cleavage of APP. In the brain, apoE is primarily produced by astrocytes and microglia, and is then lipidated by ABCA1 to form lipoprotein particles. ApoE accelerates isoform-dependent aggregation and deposition of Aβ, but also promotes the cellular uptake and clearance of Aβ by astrocytes or microglia by endocytosis of the lipidated APOE-Aβ complex. This endocytosis is mediated by various receptors, including LDLR and LRP1. ApoE facilitates isoform-dependent extracellular proteolytic degradation of Aβ. At the BBB, soluble Aβ is mostly transported via LRP1 and P-glycoprotein from the interstitial fluid (ISF) into the bloodstream. ApoE also mediates perivascular drainage of Aβ. Insufficient Aβ clearance can cause Aβ aggregation in brain parenchyma and can contribute to the formation of Aβ oligomers and amyloid plaques.