Apolipoprotein E: from lipid transport to neurobiology

Abstract

Apolipoprotein (apo) E has a storied history as a lipid transport protein. The integral association between cholesterol homeostasis and lipoprotein clearance from circulation are intimately related to apoE's function as a ligand for cell-surface receptors of the low-density lipoprotein receptor family. The receptor binding properties of apoE are strongly influenced by isoform specific amino acid differences as well as the lipidation state of the protein. As understanding of apoE as a structural component of circulating plasma lipoproteins has evolved, exciting developments in neurobiology have revitalized interest in apoE. The strong and enduring correlation between the apoE4 isoform and age of onset and increased risk of Alzheimer's disease has catapulted apoE to the forefront of neurobiology. Using genetic tools generated for study of apoE lipoprotein metabolism, transgenic "knock-in" and gene-disrupted mice are now favored models for study of its role in a variety of neurodegenerative diseases. Key structural knowledge of apoE and isoform-specific differences is driving research activity designed to elucidate how a single amino acid change can manifest such profoundly significant pathological consequences. This review describes apoE through a lens of structure-based knowledge that leads to hypotheses that attempt to explain the functions of apoE and isoform-specific effects relating to disease mechanism.

Figure 1. ApoE3 NT structures by X-ray crystallography and NMR

X-ray (left) and solution NMR (right) structures of the lipid-free N-terminal helix bundle of apoE3 displaying residues 23-164 and 1-183, respectively (PDB codes 1LPE [31] and 2KC3 [32]).

Figure 2. ApoE isoform-specific differences

Linear diagram of the apoE structural organization noting the N-terminal helical organization, functional interaction regions, isoform-specific differences at residues 112 and 158, genotypic frequencies of the human isoforms [248], and disease risk associations for the three isoforms.

Figure 3. Models of apoE helix bundle opening upon contact with lipid surfaces

The “open” (Top panel) and “extended belt” (Bottom panel) models each permit contact of hydrophobic regions of the protein with exposed hydrophobic surface. The ultimate conformation adopted by apoE on reconstituted HDL remains unresolved.

Figure 4. Aβ-independent effects of apoE4 towards neurodegeneration and pathophysiology

In healthy brain, apoE (orange) secreted from astrocytes provides support for neuronal function (Top panel). However, apoE4 increases baseline ER stress and unfolded protein response in astrocytes, slowly leading to cells that function sub-optimally (Bottom panel). As a consequence, these astrocytes are unable to provide optimal support to the neurons over a period of time. As a compensatory response, neurons generate apoE4 for self-repair, which in turn leads to increased generation of neurotoxic fragments, neurodegeneration and disease [168].

Figure 5. Schematic representation of the role of apoE3/E4-Aβ interaction in AD

ApoE isoform-specific differences (red) may influence Aβ (purple) oligomerization, deposition, transport, and/or clearance mechanisms that can influence the progression of AD. Oligomerization of Aβ released from the amyloid precursor protein (APP) in neuronal membranes has been described as a causative factor for the progression of AD and may be enhanced by apoE4 compared to apoE3. Whether apoE isoform differences affect Aβ association with apoE-HDL complexes (orange and beige) remains unclear. However clearance of apoE-Aβ HDL by lipoprotein receptors (LRP1 and LDLR) appears to be promoted to a lesser extent by apoE4 than apoE3. Astrocytes play a significant role in secreting apoE-containing HDL-sized particles.