Divergent Metabolism of Apolipoproteins E3 and E4 by Cells

Abstract

Apolipoprotein (apo-) E is a 299-amino acid, 34-kDa protein that is synthesized and secreted by hepatocytes, macrophages, and astrocytes. It is a component of both plasma and cerebrospinal fluid lipoproteins (Borghini et al, 1995; Mahley, 1988; Pitas, 1997; Pitas et al., 1987). As a component of lipoproteins, apo-E is a ligand for several members of the low density lipoprotein (LDL) receptor gene family, including the LDL receptor itself and the LDL receptor-related protein (LRP) (Krieger and Herz, 1994; Mahley, 1988; Pitas et al., 1979). Apo-E occurs in three common forms that are products of different alleles at the same gene locus (Zannis and Breslow, 1981). The proteins apo-E2, apo-E3, and apo-E4 differ by single amino acid changes at amino acids 112 and 158 (Mahley, 1988). Apo-E2 has cysteine at both positions, apo-E4 has arginine at both positions, and apo-E3 has cysteine at position 112 and arginine at 158 (Mahley, 1988; Weisgraber, 1994). These amino acid substitutions have a profound impact on the metabolic properties of the proteins and their association with disease. Of particular interest is the observation that the apo-E4 allele is overrepresented in subjects with late-onset Alzheimer’s disease (AD) and furthermore that subjects who carry the apo-E4 allele develop AD at an earlier age than those with the apo-E3 allele (Corder et al., 1993; Mayeux et al., 1993; Poirier et al., 1993; Saunders et al., 1993). Apo-E4 is therefore a major risk factor for the development of late-onset AD.

This research was funded in part by NIA Grant AG13619 and NHLBI Program Project Grant HL41633 from the National Institutes of Health. Additional funding was obtained from a Cambridge Neuroscience/Gladstone collaborative research agreement.