Abstract
Apolipoprotein (apo) E has roles beyond lipoprotein metabolism. The detrimental effects of apoE4 in cardiovascular, neurological, and infectious diseases correlate with its structural features (e.g., domain interaction) that distinguish it from apoE3 and apoE2. Structure/function studies revealed that apoE2 is severely defective in LDL receptor binding because of a structural difference that alters the receptor binding region and helped unravel the mechanism of type III hyperlipoproteinemia. ApoE4 is the major genetic risk factor for Alzheimer's disease and sets the stage for neuropathological disorders precipitated by genetic, metabolic, and environmental stressors. ApoE also influences susceptibility to parasitic, bacterial, and viral infections. In HIV-positive patients, apoE4 homozygosity hastens progression to AIDS and death and increases susceptibility to opportunistic infections. The next phase in our understanding of apoE will be characterized by clinical intervention to prevent or reverse the detrimental effects of apoE4 by modulating its structure or blocking the pathological processes it mediates.
Highlights
HISTORICAL BACKGROUNDStructural differences in apolipoprotein (apo) E isoforms impact cardiovascular, neurological, and infectious diseases [1,2,3,4]
Apolipoprotein E has roles beyond lipoprotein metabolism
Discovered in the 1970s, this 34-kDa, 299-amino-acid protein was identified in triglyceride-rich lipoproteins and induced by cholesterol feeding in animal models and humans [1, 3, 5, 6]
Summary
Structural differences in apolipoprotein (apo) E isoforms impact cardiovascular, neurological, and infectious diseases [1,2,3,4]. Gladstone investigators elucidated the structural basis for the polymorphism of apoE and showed that apoE isoforms differ at two sites: apoE3 has Cys-112 and Arg-158, whereas apoE4 has arginines at both sites, and apoE2 has cysteines [11, 12]. ApoE was shown to be involved in lipid transport and cardiovascular disease [1,2,3] It is the critical ligand in the plasma clearance of triglyceride- and cholesterol-rich lipoproteins (chylomicron remnants, VLDL, intermediate density lipoproteins, and a subclass of HDL). ApoE has a key role in neurobiology and Alzheimers disease (AD) [4] It is critical for lipid transport in the brain and contributes to neuronal maintenance and repair. The amino acid differences among the isoforms profoundly affect their structures and roles in disease
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