Lipoprotein Metabolism
Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS

https://doi.org/10.1194/jlr.R800069-JLR200Get rights and content
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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.

cholesterol
neurodegeneration
HIV
coronary heart disease
LDL receptor
dysbetalipoproteinemia
heparan sulfate proteoglycans
infectious diseases
evolution

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This work was supported in part by grant R01 AG028793 and program project grant 2P01AG02207 from the National Institutes of Health.

Abbreviations

Aβ, amyloid β

AD, Alzheimer's disease

apo, apolipoprotein

HLP, hyperlipoproteinemia

HSPG, heparan sulfate proteoglycans

HSV, herpes simplex virus

Published, JLR Papers in Press, December 22, 2008.