Apolipoprotein E (apoE), a 34 kDa glycoprotein, mediates hepatic and extrahepatic uptake of plasma lipoproteins and cholesterol efflux from lipid-laden macrophages. In humans, three structural different apoE isoforms occur, with subsequent functional changes and pathological consequences. Here, we review data supporting the involvement of apoE structural domains and isoforms in normal and altered lipid metabolism, cardiovascular and neurodegenerative diseases, as well as stress-related pathological states. Studies using truncated apoE forms provided valuable information regarding the regions and residues responsible for its properties. ApoE3 renders protection against cardiovascular diseases by maintaining lipid homeostasis, while apoE2 is associated with dysbetalipoproteinemia. ApoE4 is a recognized risk factor for Alzheimer's disease, although the exact mechanism of the disease initiation and progression is not entirely elucidated. ApoE is also implicated in infections with herpes simplex type-1, hepatitis C and human immunodeficiency viruses. Interacting with both viral and host molecules, apoE isoforms differently interfere with the viral life cycle. ApoE exerts anti-inflammatory effects, switching macrophage phenotype from the proinflammatory M1 to the anti-inflammatory M2, suppressing CD4+ and CD8+ lymphocytes, and reducing IL-2 production. The anti-oxidative properties of apoE are isoform-dependent, modulating the levels of various molecules (Nrf2 target genes, metallothioneins, paraoxonase). Mimetic peptides were designed to exploit apoE beneficial properties. The "structure correctors" which convert apoE4 into apoE3-like molecules have pharmacological potential. Despite no successful strategy is yet available for apoE-related disorders, several promising candidates deserve further improvement and exploitation.
Keywords: AD, Alzheimer's disease; ApoE; ApoE, Apolipoprotein E; CVD, cardiovascular disease; HCV, hepatitis C virus; HDL, high-density lipoprotein; HIV, human immunodeficiency virus; HLP, phospholipid transfer protein; HSPGs, heparan sulfate proteoglycans; HSV-1, herpes simplex virus type-1; Isoform; LDL, low density lipoprotein; LPG, lipoprotein glomerulopathy; LPL, lipoprotein lipase; Mimetic peptide; NS5A, nonstructural protein 5A; PLTP, type III hyperlipoproteinemia; Structural domain; TG, triglyceride; Truncated molecule; VLDL, very-low-density lipoprotein.