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.

A Potential Neuroprotective Role of Apolipoprotein E-containing Lipoproteins through Low Density Lipoprotein Receptor-related Protein 1 in Normal Tension Glaucoma

“…Human apoE3 and apoE4 isoforms differently affect neurodegeneration, particularly in Alzheimer disease (25,26). However, we found no difference in the neuroprotective efficacy of lipoproteins containing human apoE3 and apoE4 in glutamatetreated RGCs (Fig.…”

Recent advances in physiological lipoprotein metabolism

“…ApoE3 contains a cysteine at position 112 and an arginine at 158, while apoE2 contains cysteine at both sites and apoE4 contains arginine at these sites. ApoE3 is considered the wild type isoform in humans because of its high allelic frequency and lack of human disease phenotype [124]. It was proposed that apoE contains two domains an N-terminal domain (a four-helix bundle) and C-terminal domain linked by a flexible hinge region.…”

Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry

“…This disrupts the lipolysis cascade involved in the catabolism of VLDL and impairs its clearance, producing higher plasma cholesterol levels and increased risk of cardiovascular disease (3,8). In addition, the expression of apoE4 in the brain is the major genetic risk factor for early onset Alzheimer's disease (9,10). ApoE4 leads to reduced clearance of extracellular amyloid plaque deposits in the brain (10), increases neuronal degeneration (11), and reduces longevity (12).…”