ReviewApolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases
Introduction
ApoE functions as a component of plasma lipoproteins in the transport of lipids among cells of different organs and within specific tissues (Mahley, 1988, Mahley and Huang, 1999, Mahley and Ji, 1999, Mahley and Rall, 2001, Mahley et al., 1999, Weisgraber, 1994). Discovered in the early 1970s, it is one of several apolipoproteins associated with very low density lipoproteins (VLDLs), intermediate density lipoproteins, chylomicron remnants, and certain subclasses of high-density lipoproteins (HDLs). ApoE plays a key role in regulating the clearance of these lipoproteins from the plasma by serving as the ligand for binding to specific cell-surface receptors, including the LDL receptor family members and heparan sulfate proteoglycans (HSPGs) (Mahley, 1988, Mahley and Huang, 1999, Mahley and Ji, 1999, Mahley and Rall, 2001, Mahley et al., 1999, Weisgraber, 1994).
ApoE3, the most common of the three isoforms, is considered to be the normal form. ApoE2 and apoE4 differ from apoE3 by single amino acid substitutions at position 112 or 158 (Fig. 1). Early studies established the amino acid and structural differences among the various apoE isoforms and advanced our understanding of the roles of apoE in various metabolic pathways. Understanding of the role of apoE in lipid metabolism was further advanced by the discovery that apoE2 is defective in lipoprotein receptor binding and is associated with the genetic disorder type III hyperlipoproteinemia (Mahley, 1988, Mahley and Rall, 2001, Mahley et al., 1999). The genetic linkage of apoE4 to the pathogenesis of AD has refocused attention on the importance of this apolipoprotein in neurobiology and neurodegenerative diseases (Fig. 1) (Bu, 2009, Herz and Berffert, 2000, Huang, 2010, Huang and Mucke, 2012, Huang et al., 2004, Kim et al., 2009, Mahley and Huang, 2012a, Mahley et al., 2006, Roses, 1996).
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Synthesis of ApoE in different tissues and cells
ApoE is synthesized and secreted from a variety of tissues and several types of cells and is abundant in the interstitial fluid and lymph, as well as in the plasma (Huang, 2010, Huang and Mucke, 2012, Huang et al., 2004, Mahley, 1988, Mahley and Huang, 1999, Mahley and Huang, 2012a, Mahley et al., 2006). ApoE may be secreted by cells in a lipid-poor form; however, because of its avidity for lipids (especially phospholipids), apoE almost certainly always exists in association with lipids and
Structure and function of ApoE isoforms in lipid metabolism
A major function of apoE is to transport lipids among various cells and tissues of the body (Herz and Bock, 2002, Mahley, 1988, Mahley and Huang, 1999, Mahley and Ji, 1999, Mahley and Rall, 2001, Mahley et al., 1999, Weisgraber, 1994). ApoE is a key regulator of plasma lipid levels and participates in the homeostatic control of plasma and tissue lipid content. This is accomplished in part because apoE binds with high affinity to cell-surface lipoprotein receptors. ApoE mediates the interaction
Receptor and heparan sulfate proteoglycan binding activity
ApoE possesses two structural domains that are connected by 20 to 30 amino acids that may serve as a hinge between the two domains. The N-terminal two thirds of apoE contains the receptor binding region. Six to eight critical arginine and lysine residues and a histidine residue in the region of amino acids 136–150 mediate the interaction of apoE with the ligand binding domain of the LDL receptor (Mahley, 1988, Mahley and Huang, 1999, Mahley and Ji, 1999, Mahley and Rall, 2001, Mahley et al.,
Lipid and lipoprotein binding activity
The isoforms of apoE display preferences for specific classes of lipoproteins (Mahley, 1988, Mahley and Huang, 1999, Mahley and Ji, 1999, Mahley and Rall, 2001, Mahley et al., 1999, Weisgraber, 1994). Examination of the distribution of apoE among the various plasma lipoproteins has shown that apoE4 has a preference for large, triglyceride-rich VLDL particles, whereas apoE3 and apoE2 associate preferentially with the small, phospholipid-rich HDL.
The C-terminal one third of the apoE molecule is
Intramolecular domain interaction may explain ApoE isoform-specific activities
The residues that distinguish the apoE isoforms are in the N-terminus (apoE4, arginine 112; apoE3 and apoE2, cysteine 112). However, the lipid-binding region is in the C-terminus (residues 244–272). This suggests that the N- and C-terminal domains interact to determine the preference of apoE4 for VLDL and of apoE3 and apoE2 for HDL.
Comparison of the three-dimensional structures of the N-terminal domains of apoE3 and apoE4 and site-directed mutagenesis have provided insights into the functional
Structure and function of ApoE in neurobiology and Alzheimer's disease
Several lines of evidence have linked apoE to neurobiology and Alzheimer's disease. By the mid-1980s, clues had begun to surface that apoE plays an important role in neurological diseases. ApoE is produced in abundance in the brain and serves as the principal lipid transport vehicle in CSF. It is induced at a high concentration in peripheral nerve injury and appears to play a key role in repair by redistributing lipids to regenerating axons and to Schwann cells during remyelination. It
Aβ-dependent effects of apoE4 on AD pathogenesis
Aβ overproduction and deposition may play a central role in AD pathogenesis (Bu, 2009, Kim et al., 2009, Selkoe, 2001). Clearly, apoE has isoform-specific effects on Aβ metabolism and catabolism, as it exacerbates Aβ-caused neuropathology and cognitive decline. In vivo, apoE is associated with neuritic amyloid plaques (Namba et al., 1991, Strittmatter et al., 1993a, Wisniewski and Frangione, 1992). In vitro, lipid-free apoE3 and apoE4 can form stable complexes with Aβ peptides; these complexes
Aβ-independent effects of ApoE4 on AD pathogenesis
Both in vivo and in vitro studies also suggest Aβ-independent roles of apoE4 in AD pathogenesis. The Aβ-independent detrimental effects may act in parallel with Aβ-dependent effects of apoE4, leading to neuropathology and cognitive decline.
ApoE4 and other neurodegenerative disorders
Although the data are not as strong as with AD, apoE4 has also been associated with progression or poor clinical outcomes in other neurological or neurodegenerative diseases, including traumatic brain injury (TBI) (Chamelian et al., 2004, Crawford et al., 2002, Friedman et al., 1999, Gandy and DeKosky, 2012, Mayeux et al., 1995, Nicoll et al., 1996, Teasdale et al., 1997), multiple sclerosis (Chapman et al., 2001, Fazekas et al., 2001), stroke (Alberts et al., 1995, McCarron et al., 1999,
Other lipid metabolism-related genes and AD
AD appears to be linked to cholesterol metabolism-related genes other than apoE (Shobab et al., 2005, Wolozin, 2004). It has been reported that AD is associated with a polymorphism in ABCA1 (ATP-binding cassette, subfamily A, member 1), a cellular cholesterol transporter (Katzov et al., 2004); however, that association was not found in another study (Y. Li et al., 2004). In mice, ABCA1 is required for maintaining normal CNS apoE levels and for lipidation of astrocyte-secreted apoE (
Conclusion and Perspective
Biochemical, cell biological, and transgenic animal studies have suggested several mechanisms to explain the contribution of apoE4 to AD pathogenesis (Bu, 2009, Huang, 2010, Huang and Mucke, 2012, Huang et al., 2004, Kim et al., 2009, Mahley and Huang, 2012a, Mahley et al., 2006). However, the mechanisms of these apoE4-mediated effects are still poorly understood. Likewise, it is not known which of these pathophysiological effects of apoE4 is the primary effect and which are subsequent or
Acknowledgment
This work was supported in part by the National Institutes of Heath grants P50AG023501, 1RF1AG047655, and 2P50AG023501, the S.D. Bechtel, Jr. Foundation, and the Hellman Foundation. We thank Linda Turney for manuscript preparation, Gary Howard for editorial assistance, and John C.W. Carroll for graphics.
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