Elsevier

Neurobiology of Disease

Volume 72, Part A, December 2014, Pages 3-12
Neurobiology of Disease

Review
Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases

https://doi.org/10.1016/j.nbd.2014.08.025Get rights and content

Abstract

Apolipoprotein (apo) E is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It has three major isoforms (apoE2, apoE3, and apoE4) with different effects on lipid and neuronal homeostasis. A major function of apoE is to mediate the binding of lipoproteins or lipid complexes in the plasma or interstitial fluids to specific cell-surface receptors. These receptors internalize apoE-containing lipoprotein particles; thus, apoE participates in the distribution/redistribution of lipids among various tissues and cells of the body. In addition, intracellular apoE may modulate various cellular processes physiologically or pathophysiologically, including cytoskeletal assembly and stability, mitochondrial integrity and function, and dendritic morphology and function. Elucidation of the functional domains within this protein and of the three-dimensional structure of the major isoforms of apoE has contributed significantly to our understanding of its physiological and pathophysiological roles at a molecular level. It is likely that apoE, with its multiple cellular origins and multiple structural and biophysical properties, is involved widely in processes of lipid metabolism and neurobiology, possibly encompassing a variety of disorders of neuronal repair, remodeling, and degeneration by interacting with different factors through various pathways.

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).

Section snippets

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.

References (151)

  • A.M. Fagan et al.

    Unique lipoproteins secreted by primary astrocytes from wild type, apoE (−/−), and human apoE transgenic mice

    J. Biol. Chem.

    (1999)
  • A.D. Frankel et al.

    Cellular uptake of the tat protein from human immunodeficiency virus

    Cell

    (1988)
  • M. Green et al.

    Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein

    Cell

    (1988)
  • D. Grouselle et al.

    Loss of somatostatin-like immunoreactivity in the frontal cortex of Alzheimer patients carrying the apolipoprotein epsilon 4 allele

    Neurosci. Lett.

    (1998)
  • J. Hardy et al.

    A disorder of cortical GABAergic innervation in Alzheimer's disease

    Neurosci. Lett.

    (1987)
  • F.M. Harris et al.

    Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: Modulation by zinc

    J. Biol. Chem.

    (2004)
  • R.E. Hartman et al.

    Behavioral phenotyping of GFAP-apoE3 and -apoE4 transgenic mice: ApoE4 mice show profound working memory impairments in the absence of Alzheimer's-like neuropathology

    Exp. Neurol.

    (2001)
  • V. Hirsch-Reinshagen et al.

    Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain

    J. Biol. Chem.

    (2004)
  • V. Hirsch-Reinshagen et al.

    The absence of ABCA1 decreases soluble apoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease

    J. Biol. Chem.

    (2005)
  • Y. Huang

    Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease

    Trends Mol. Med.

    (2010)
  • Y. Huang et al.

    Alzheimer mechanisms and therapeutic strategies

    Cell

    (2012)
  • Y. Ji et al.

    Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients

    Neuroscience

    (2003)
  • K. Kamino et al.

    Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population

    Biochem. Biophys. Res. Commun.

    (2000)
  • J. Kim et al.

    The role of apolipoprotein E in Alzheimer's disease

    Neuron

    (2009)
  • R. Koldamova et al.

    Lack of ABCA1 considerably decreases brain apoE level and increases amyloid deposition in APP23 mice

    J. Biol. Chem.

    (2005)
  • M.J. LaDu et al.

    Isoform-specific binding of apolipoprotein E to β-amyloid

    J. Biol. Chem.

    (1994)
  • G. Li et al.

    GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice

    Cell Stem Cell

    (2009)
  • Y. Li et al.

    Association of ABCA1 with the late-onset Alzheimer's disease is not observed in a case–control study

    Neurosci. Lett.

    (2004)
  • R.W. Mahley et al.

    Apolipoprotein E sets the stage: response to injury triggers neuropathology

    Neuron

    (2012)
  • R.W. Mahley et al.

    Remnant lipoprotein metabolism: Key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E

    J. Lipid Res.

    (1999)
  • R.W. Mahley et al.

    Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): Questions, quandaries, and paradoxes

    J. Lipid Res.

    (1999)
  • F. Agosta et al.

    Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer's disease and frontotemporal dementia

    Proc. Natl. Acad. Sci. U. S. A.

    (2009)
  • Y. Andrews-Zwilling et al.

    Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice

    J. Neurosci.

    (2010)
  • K.R. Bales et al.

    Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer's disease

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • S.R. Bareggi et al.

    Decreased CSF concentrations of homovanillic acid and γ-aminobutyric acid in Alzheimer's disease. Age- or disease-related modifications?

    Arch. Neurol.

    (1982)
  • R.D. Bell et al.

    Apolipoprotein E controls cerebrovascular integrity via yclophilin A

    Nature

    (2012)
  • N. Bien-Ly et al.

    Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice

    J. Neurosci.

    (2012)
  • A. Boehm-Cagan et al.

    Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene

    J. Neurosci.

    (2014)
  • W.J. Brecht et al.

    Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice

    J. Neurosci.

    (2004)
  • J. Brodbeck et al.

    Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons

    PNAS

    (2008)
  • G. Bu

    Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy

    Nat. Rev. Neurosci.

    (2009)
  • M. Buttini et al.

    Expression of human apolipoprotein E3 or E4 in the brains of Apoe−/− mice: Isoform-specific effects on neurodegeneration

    J. Neurosci.

    (1999)
  • M. Buttini et al.

    Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid β peptides but not on plaque formation

    J. Neurosci.

    (2002)
  • J.M. Castellano et al.

    Human apoE isoforms differentially regulate brain amyloid-β peptide clearance

    Sci. Transl. Med.

    (2011)
  • L. Chamelian et al.

    Six-month recovery from mild to moderate traumatic brain injury: the role of APOE-ε4 allele

    Brain

    (2004)
  • S. Chang et al.

    Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • J. Chapman et al.

    APOE genotype is a major predictor of long-term progression of disability in MS

    Neurology

    (2001)
  • Y. Chen et al.

    ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively imparing apoE receptor recycling

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • H.S. Cho et al.

    Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in Aβ aggregation

    J. Neuropathol. Exp. Neurol.

    (2001)
  • P.E. Cramer et al.

    ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models

    Science

    (2012)
  • Cited by (0)

    View full text