Apolipoprotein E: Remarkable Protein Sheds Light on Cardiovascular and Neurological Diseases

[摘要] Apolipoprotein E (apoE)6 is a relatively small protein (34 kDa, 299 amino acids) that has been slowly revealing its biologic secrets in cardiovascular and neurological diseases over the past 45 years since it was first observed as a protein constituent of plasma lipoproteins. ApoE is encoded by a single gene on chromosome 19 [apolipoprotein E ( APOE )]. Its seemingly complex isoform polymorphism involves 3 isoforms that differ by single amino acid interchanges at residues 112 and 158, resulting from single base changes in the APOE gene. ApoE3, the most common isoform (ε3 prevalence 65%–70% in the population), differs from apoE4 (ε4 prevalence 15%–20%) at residue 112, where cysteine in apoE3 is substituted for arginine. ApoE3 differs from apoE2 (ε2 prevalence 8%–10%) at residue 158, where arginine in apoE3 is substituted for cysteine. ApoE4 increases the risk of cardiovascular disease and is associated with increased concentrations of LDL; it also increases risk for Alzheimer disease (AD) and decreases the age of onset and is associated with increased severity or progression of numerous other neurodegenerative disorders. ApoE2 is associated with the genetic disorder type III hyperlipoproteinemia and accelerated atherosclerosis and is “protective” against the development of AD. The structure of apoE and its function in cardiovascular and neurological diseases were elucidated with my distinguished long-term colleagues: Thomas Innerarity, Karl Weisgraber, Stanley Rall, Robert Pitas, Thomas Bersot, and Yadong Huang (Fig. 1) [for reviews, see (1–3)].Fig. 1. Dr. Robert Mahley and his colleagues at the Gladstone Institutes.My first encounter with the protein that would eventually be known as apoE was at Vanderbilt University Medical School during my MD–PhD studies in 1970. My thesis project was to demonstrate that the liver was the source of plasma VLDL by showing that the particles seen in the rat liver Golgi apparatus were nascent VLDL (the Golgi apparatus is now routinely isolated but then …

[学科分类] 过敏症与临床免疫学