Human APOE is a 34 kDa glycoprotein1 that is composed of 299 amino acids after cleavage of the 18-amino-acid signal peptide. In the CNS, APOE is abundantly expressed in astrocytes, microglia, vascular mural cells and choroid plexus cells, and to a lesser extent in stressed neurons2, 3. Once APOE has been secreted from the cells, the cell surface ATP-binding cassette transporters ABCA14 and ABCG15 transfer cholesterol and phospholipids to nascent APOE to form lipoprotein particles. The size and density of APOE lipoprotein particles in the cerebrospinal fluid (CSF) are similar to those of HDL6. APOE plays a critical role in redistributing cholesterol and other lipids to neurons through binding to cell-surface APOE receptors. The LDL receptor (LDLR) family members, including LDLR and LDLR-related protein 1 (LRP1), are major APOE receptors involved in APOE-mediated lipid metabolism. APOE has two main functional regions: the receptor-binding region in the amino-terminal domain and the lipid-binding region in the carboxy-terminal domain7, 8.

Computer-assisted modelling has been performed to examine the conformational changes in APOE that potentially occur on lipid binding. Structural modelling of human APOE3 was accomplished using data on APOE from the Protein Data Bank9-16. The modelling technique has  been well documented17-23 and enables composite protein structures to be built from multiple structural templates. The resulting lipid-free and lipid-bound structures are shown in figure below24-27. The structures show that the lipid-binding region (residues 244272) of APOE interacts directly with the lipid particle. Lipid binding to APOE increases the accessibility of the receptor-binding region (residues 136150), thereby enabling cellular lipid delivery. The structural changes to APOE that are predicted to take place on lipid binding are consistent with those documented in the existing structural literature for this protein9, 10, 13, 14, 16, 28-33.

The APOE isoforms encoded by the three corresponding gene alleles differ from one another only at positions 112 and 158 (APOE2: Cys112, Cys158; APOE3: Cys112, Arg158; APOE4: Arg112, Arg158). However, these single amino acid polymorphisms substantially alter the structure and function of APOE, thereby modulating its binding properties with regard to both lipids and receptors. For example, the binding of APOE2 to LDLR is more than 50 times weaker than the binding  of APOE3 or APOE4 to this receptor34. In the periphery, the relatively low affinity of APOE2 for LDLR impairs the clearance of triglyceride-rich lipoprotein remnant particles and, as a consequence, APOE2 contributes to the onset of type III hyperlipoproteinaemia1, 35. By contrast, enhanced binding of APOE4 to VLDL particles, as compared with the other APOE isoforms34, impairs lipolytic processing of VLDL in the periphery; thus, APOE4 is associated with pro-atherogenic changes in lipoprotein distribution35.

In addition to their role in lipid homeostasis in the periphery, APOE isoforms differentially modulate multiple pathways in the brain, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. However, the correlation between the structure of individual APOE isoforms and their modulation of these pathways in the brain is less clear than for their actions on peripheral lipid metabolism. Possible mechanisms by which structural differences between APOE isoforms could modulate these brain pathways include differences in protein conformation, post-translational modification, lipoprotein preference and binding affinity for receptors8.

Studies have also shed light on the potential role of plasma APOE in brain homeostasis. Synaptic dysfunction in Apoe-knockout mice can be partially restored, and cognition improved, by genetic restoration of peripheral APOE36. These effects occur despite the presence of the bloodbrain barrier (BBB), which blocks APOE influx from the periphery. The relative ratio of APOE4 to APOE3 in plasma positively correlates with the loss of regional grey matter volume and abnormal cerebral glucose metabolism in cognitively healthy APOE*ε3/ε4 carriers37, linking the isoform composition of plasma APOE to structural and metabolic changes of the brain. Therefore, plasma APOE is a potential determinant of brain structure and function.

In APOE*ε3/ε4 individuals, the APOE4:APOE3 ratio is >1 in the brain and CSF but <1 in the plasma38, 39, suggesting that the metabolic pathways of APOE isoforms differ between the CNS and plasma. Thus, further studies exploring the similarities and differences in APOE metabolism between the CNS and periphery, and the functional crosstalk between brain and plasma APOE, would aid a better understanding of the impact of APOE isoforms on brain physiology.

Yamazaki, Y., et al. (2019). “Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.” Nat Rev Neurol 15(9): 501-518.

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