Alzheimer's disease is a debilitating neurodegenerative disorder that afflicts an increasing part of our ageing population. An isoform of apolipoprotein E, a protein that mediates the transport of lipids and cholesterol in the circulatory system, predisposes carriers of this allele to the common late-onset form of the disease. How this protein is related to a neurodegenerative disorder is an enigma. Mounting evidence indicates that apolipoprotein E receptors, which are abundantly expressed in most neurons in the central nervous system, also fulfil critical functions during brain development and may profoundly influence the pathogenesis of Alzheimer's disease.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D. & Mahley, R. W. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim. Biophys. Acta 917, 148–161 (1987).
Pitas, R. E., Ji, Z. S., Weisgraber, K. H. & Mahley, R. W. Role of apolipoprotein E in modulating neurite outgrowth: potential effect of intracellular apolipoprotein E. Biochem. Soc. Trans. 26, 257–262 (1998).
Boyles, J. K. et al. A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J. Clin. Invest. 83, 1015–1031 (1989).
Wolf, B. B., Lopes, M. B. S., VandenBerg, S. R. & Gonias, S. L. Characterization and immunohistochemical localization of α2-macroglobulin receptor (low density lipoprotein receptor-related protein) in human brain . Am. J. Pathol. 141, 37– 42 (1992).
Schmechel, D. E. et al. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease . Proc. Natl Acad. Sci. USA 90, 9649– 9653 (1993).
Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993). References 5 and 6 describe how ApoE4 is found to predispose carriers to late-onset AD.
Mahley, R. W. & Rall, S. C. in The Metabolic and Molecular Bases of Inherited Disease (eds Scriver, C. R., Beaudet, A. R., Sly, W. S. & Valle, D.) 1952–1980 (McGraw-Hill, New York, 1995).
Kounnas, M. Z. et al. LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation . Cell 82, 331–340 (1995).
Blacker, D. et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nature Genet. 19, 357– 360 (1998).
Kristensen, T. et al. Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the α2-macroglobulin receptor. FEBS Lett. 276, 151–155 (1990).
Strickland, D. K. et al. Sequence identity between the α2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J. Biol. Chem. 265, 17401–17404 (1990).
Kang, D. E. et al. Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease. Neurology 49, 56– 61 (1997).
Herz, J., Clouthier, D. E. & Hammer, R. E. LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation Cell 71, 411–421 ( 1992). Erratum, 73, 428 (1993).
Ishibashi, S. et al. Hypercholesterolemia in LDL receptor knockout mice And its reversal by adenovirus-mediated gene delivery. J. Clin. Invest. 92, 883–893 ( 1993).
Frykman, P. K., Brown, M. S., Yamamoto, T., Goldstein, J. L. & Herz, J. Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor. Proc. Natl Acad. Sci. USA 92, 8453–8457 (1995).
Willnow, T. E. et al. Defective forebrain development in mice lacking gp330/megalin . Proc. Natl Acad. Sci. USA 93, 8460– 8464 (1996).
Trommsdorff, M. et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97, 689–701 (1999). Double knockout mice lacking the VLDL receptor and ApoE receptor-2 show a phenotype indistinguishable from reeler and Dab1-deficient mice. Dab1 is shown to bind to the cytoplasmic tails of both receptors indicating that reelin, the VLDL receptor and ApoER2, and Dab1 may function in a linear signalling pathway.
Nykjaer, A. et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 96, 507–515 (1999).
Krieger, M. & Herz, J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu. Rev. Biochem. 63, 601 –637 (1994).
Willnow, T. E. The low-density lipoprotein receptor gene family: multiple roles in lipid metabolism. J. Mol. Med. 77, 306– 315 (1999).
Willnow, T. E., Nykjaer, A. & Herz, J. Lipoprotein receptors: new roles for ancient proteins . Nature Cell Biol. 1, E157– E162 (1999).
D'Arcangelo, G. et al. Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J. Neurosci. 17, 23 –31 (1997).
Rice, D. S. & Curran, T. Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS. Genes Dev. 13, 2758– 2773 (1999).
Ware, M. L. et al. Aberrant splicing of a mouse disabled homolog, mdab1, in the scrambler mouse. Neuron 19, 239– 249 (1997).
Sheldon, M. et al. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature 389, 730–733 (1997).
Howell, B. W., Hawkes, R., Soriano, P. & Cooper, J. A. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389, 733–737 ( 1997).References 24–26 report that inactivating mutations in the cytoplasmic adaptor protein Dab1 cause a reeler -like phenotype in mice. This genetic evidence implicates Dab1 as a probable downstream component of a pathway that transduces the reelin signal.
Falconer, D. S. Two new mutants ‘trembler’ and ‘reeler’ with neurological actions in the house mouse. J. Genet. 50, 192–201 (1951).
Hiesberger, T. et al. Direct binding of reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation . Neuron 24, 481–489 (1999).
D'Arcangelo, G. et al. Reelin is a ligand for lipoprotein receptors. Neuron 24, 471–479 ( 1999).References 28 and 29 report that reelin binds to the extracellular domains of the VLDL receptor and ApoER2. Mutation in the reelin signalling pathway is shown to cause hyperphosphorylation of the microtubule-stabilizing protein tau. ApoE interferes with reelin signalling.
Howell, B. W., Herrick, T. M. & Cooper, J. A. Reelin-induced tyrosine phosphorylation of disabled 1 during neuronal positioning. Genes Dev. 13, 643–648 (1999).
Trommsdorff, M., Borg, J. P., Margolis, B. & Herz, J. Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J. Biol. Chem. 273, 33556–33560 (1998).
Chen, W. J., Goldstein, J. L. & Brown, M. S. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J. Biol. Chem. 265, 3116– 3123 (1990).
Pawson, T. & Scott, J. D. Signaling through scaffold, anchoring, and adaptor proteins. Science 278, 2075– 2080 (1997).
Pawson, T. & Nash, P. Protein–protein interactions define specificity in signal transduction. Genes Dev. 14, 1027–1047 (2000).
Guenette, S. Y., Chen, J., Jondro, P. D. & Tanzi, R. E. Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein. Proc. Natl Acad. Sci. USA 93, 10832–10837 (1996).
Bressler, S. L. et al. cDNA cloning and chromosome mapping of the human Fe65 gene: interaction of the conserved cytoplasmic domains of the human beta-amyloid precursor protein and its homologues with the mouse Fe65 protein. Hum. Mol. Genet. 5, 1589–1598 (1996).
Gotthardt, M. et al. Interactions of the low density lipoprotein (LDL) receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction. J. Biol. Chem. 275, 25616–25624 (2000).
Howell, B. W., Lanier, L. M., Frank, R., Gertler, F. B. & Cooper, J. A. The disabled 1 phosphotyrosine-binding domain binds to the internalization signals of transmembrane glycoproteins and to phospholipids . Mol. Cell Biol. 19, 5179– 5188 (1999).
Senzaki, K., Ogawa, M. & Yagi, T. Proteins of the CNR family are multiple receptors for Reelin. Cell 99, 635–647 ( 1999).
Chae, T. et al. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18, 29–42 ( 1997).
Ohshima, T. et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death . Proc. Natl Acad. Sci. USA 93, 11173– 11178 (1996).
Gilmore, E. C., Ohshima, T., Goffinet, A. M., Kulkarni, A. B. & Herrup, K. Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex. J. Neurosci. 18, 6370–6377 (1998).References 40–42 report the generation of mutant mice in which the activity of the cytoplasmic kinase cdk5 is impaired. This results in lamination defects resembling certain aspects of the reeler phenotype.
Nikolic, M., Dudek, H., Kwon, Y. T., Ramos, Y. F. & Tsai, L. H. The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev. 10, 816–825 (1996).
Patrick, G. N. et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615– 622 (1999).
Stockinger, W. et al. The reelin receptor ApoER2 recruits JNK-interacting proteins-1 and 2. J. Biol. Chem. 275, 25625– 25632 (2000).
D'Arcangelo, G. et al. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374, 719–723 (1995).
Ulery, P. G. et al. Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease. J. Biol. Chem. 275, 7410–7415 (2000).
Selkoe, D. J. Translating cell biology into therapeutic advances in Alzheimer's disease . Nature 399, A23–A31 (1999).
Vassar, R. et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).
Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 402, 533– 537 (1999).
Sinha, S. et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402, 537– 540 (1999).References 49–51 report the identification and cloning of a membrane-bound protease that mediates the cleavage of APP at the β-secretase cleavage site.
Parvathy, S., Hussain, I., Karran, E. H., Turner, A. J. & Hooper, N. M. Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells . Biochemistry 38, 9728– 9734 (1999).
LaMarre, J., Wolf, B. B., Kittler, E. L. W., Quesenberry, P. J. & Gonias, S. L. Regulation of macrophage α2-macroglobulin receptor/low density lipoprotein receptor-related protein by lipopolysaccharide and interferon-γ. J. Clin. Invest. 91, 1219–1224 (1993).
Roses, A. D. & Saunders, A. Head injury, amyloid beta and Alzheimer's disease. Nature Med. 1, 603– 604 (1995).
Guenette, S. Y. et al. hFE65L influences amyloid precursor protein maturation and secretion. J. Neurochem. 73, 985– 993 (1999).
Sabo, S. L. et al. Regulation of beta-amyloid secretion by FE65, an amyloid protein precursor-binding protein. J. Biol. Chem. 274, 7952–7957 (1999). In references 55 and 56, FE65 family members are shown to alter APP processing and increase the surface residence time of APP.
Homayouni, R., Rice, D. S., Sheldon, M. & Curran, T. Dab1 binds to the cytoplasmic domain of the amyloid precursor-like protein 1. J. Neurosci. 19, 7507–7515. (1999).
Zambrano, N., Minopoli, G., de Candia, P. & Russo, T. The Fe65 adaptor protein interacts through its PID1 domain with the transcription factor CP2/LSF/LBP1. J. Biol. Chem. 273, 20128–20133 (1998).
Lau, K. F., Miller, C. C., Anderton, B. H. & Shaw, P. C. Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter. Genomics 60, 121– 128 (1999).
Holtzman, D. M. et al. Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. Proc. Natl Acad. Sci. USA 92, 9480–9484 (1995).
Nathan, B. P., Bellosta, S., Sanan, D. A., Mahley, R. W. & Pitas, R. E. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264, 850–852 (1994).
Bellosta, S. et al. Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth . J. Biol. Chem. 270, 27063– 27071 (1995).
LaDu, M. J. et al. Isoform-specific binding of apolipoprotein E to β-amyloid . J. Biol. Chem. 269, 23403– 23406 (1994).
Qiu, W. Q. et al. Degradation of amyloid beta-protein by a serine protease-alpha2-macroglobulin complex. J. Biol. Chem. 271, 8443– 8451 (1996).
Postuma, R. B. et al. Effects of the amyloid protein precursor of Alzheimer's disease and other ligands of the LDL receptor-related protein on neurite outgrowth from sympathetic neurons in culture. FEBS Lett. 428 , 13–16 (1998).
Stockinger, W. et al. The low density lipoprotein receptor gene family. Differential expression of two alpha2-macroglobulin receptors in the brain. J. Biol. Chem. 273, 32213–32221 (1998).
Bales, K. R. et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nature Genet. 17, 263– 264 (1997).ApoE knockout mice are protected from plaque formation in an APP-overexpressing animal model. This study convincingly shows a direct effect of ApoE on the formation of amyloid lesions in the brain.
Lippa, C. F. et al. Apolipoprotein E-epsilon 2 and Alzheimer's disease: genotype influences pathologic phenotype. Neurology 48, 515–519 (1997).
Harada, A. et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369, 488 –491 (1994).
Hong, M. et al. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914 –1917 (1998).
Ishihara, T. et al. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24, 751–762 ( 1999).
Genis, I., Gordon, I., Sehayek, E. & Michaelson, D. M. Phosphorylation of tau in apolipoprotein E-deficient mice. Neurosci. Lett. 199, 5–8 (1995).
Zhuo, M. et al. Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation. J. Neurosci. 20, 542–549 (2000).
Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398, 513–517 ( 1999).
Brown, M. S. & Goldstein, J. L. A receptor-mediated pathway for cholesterol homeostasis. Science 232, 34–47 (1986).
Herz, J. et al. Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J. 7, 4119–4127 (1988).
Kim, D. H. et al. Human apolipoprotein E receptor 2. A novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in brain. J. Biol. Chem. 271, 8373– 8380 (1996).
Saito, A., Pietromonaco, S., Loo, A. K. & Farquhar, M. G. Complete cloning and sequencing of rat gp330/‘megalin,’ a distinctive member of the low density lipoprotein receptor gene family. Proc. Natl Acad. Sci. USA 91, 9725–9729 (1994).
Takahashi, S., Kawarabayasi, Y., Nakai, T., Sakai, J. & Yamamoto, T. Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein with distinct ligand specificity. Proc. Natl Acad. Sci. USA 89, 9252–9256 (1992).
Novak, S., Hiesberger, T., Schneider, W. J. & Nimpf, J. A new low density lipoprotein receptor homologue with 8 ligand binding repeats in brain of chicken and mouse J. Biol. Chem. 271, 11732–11736 (1996). Erratum, 271, 27188 (1996).
Schonbaum, C. P., Lee, S. & Mahowald, A. P. The Drosophila yolkless gene encodes a vitellogenin receptor belonging to the low density lipoprotein receptor superfamily. Proc. Natl Acad. Sci. USA 92, 1485– 1489 (1995).
Yochem, J. & Greenwald, I. A gene for a low density lipoprotein receptor-related protein in the nematode Caenorhabditis elegans. J. Biol. Chem. 268, 13002– 13009 (1993).
Rubin, G. M. et al. Comparative genomics of the eukaryotes. Science 287, 2204–2215 ( 2000).
Ermekova, K. S. et al. The WW domain of neural protein FE65 interacts with proline-rich motifs in Mena, the mammalian homolog of Drosophila enabled. J. Biol. Chem. 272, 32869–32877 (1997).
Ahern-Djamali, S. M. et al. Mutations in Drosophila enabled and rescue by human vasodilator-stimulated phosphoprotein (VASP) indicate important functional roles for Ena/VASP homology domain 1 (EVH1) and EVH2 domains. Mol. Biol. Cell 9, 2157–2171 (1998).
Gertler, F. B., Doctor, J. S. & Hoffmann, F. M. Genetic suppression of mutations in the Drosophila abl proto-oncogene homolog. Science 248, 857–860 (1990).
Gertler, F. B., Hill, K. K., Clark, M. J. & Hoffmann, F. M. Dosage-sensitive modifiers of Drosophila abl tyrosine kinase function: prospero, a regulator of axonal outgrowth, and disabled, a novel tyrosine kinase substrate Genes Dev. 7, 441– 453 (1993). Erratum, 10, 2234 (1996).
Gertler, F. B., Niebuhr, K., Reinhard, M., Wehland, J. & Soriano, P. Mena, a relative of VASP and Drosophila Enabled, is implicated in the control of microfilament dynamics . Cell 87, 227–239 (1996).
Lanier, L. M. et al. Mena is required for neurulation and commissure formation . Neuron 22, 313–325 (1999).
Yasuda, J., Whitmarsh, A. J., Cavanagh, J., Sharma, M. & Davis, R. J. The JIP group of mitogen-activated protein kinase scaffold proteins. Mol. Cell. Biol. 19, 7245–7254 (1999).
Lammich, S. et al. Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl Acad. Sci. USA 96, 3922–3927 (1999).
Buxbaum, J. D. et al. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha–secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 27765 –27767 (1998).
Beffert, U., Arguin, C. & Poirier, J. The polymorphism in exon 3 of the low density lipoprotein receptor-related protein gene is weakly associated with Alzheimer's disease . Neurosci. Lett. 259, 29– 32 (1999).
Fiore, F. et al. The regions of the Fe65 protein homologous to the phosphotyrosine interaction/phosphotyrosine binding domain of Shc bind the intracellular domain of the Alzheimer's amyloid precursor protein. J. Biol. Chem. 270, 30853–30856 (1995). A PTB domain in FE65 is shown to bind to the NPxY motif in APP.
Hu, Q. et al. The human FE65 gene: genomic structure and an intronic biallelic polymorphism associated with sporadic dementia of the Alzheimer type. Hum. Genet. 103, 295–303 (1998).
Scott, W. K. et al. Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am. J. Hum. Genet. 66, 922–932 ( 2000).
Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genet. 25, 402–405 (2000).
Supported by grants from the NIH, the Human Frontier Science Program, the Perot Family Foundation and the American Heart Association. U.B. is supported by a fellowship from the Human Frontier Science Program.
- GENETIC LINKAGE
The association of two or more genes such that they are normally transmitted together.
- KUNITZ-TYPE PROTEASE INHIBITOR DOMAIN
An alternatively transcribed exon within APP that encodes a protease inhibitor. APP is also known as protease nexin II, and is a potent inhibitor of blood coagulation factors IXa and XIa.
The existence of different genotypes in frequencies that cannot be explained by recurrent mutations.
Failure of the forebrain or prosencephalon to divide into hemispheres or lobes, often accompanied by a deficit in midline facial development.
- CEREBELLAR ATAXIA
Loss of muscle coordination caused by disorders of the cerebellum.
A tetra-amino-acid motif present in the cytoplasmic tail of the LDL receptor family and other cell surface receptors mediating endocytosis and interactions with PTB-domain-containing adaptor and scaffold proteins.
- WW DOMAIN
Domains containing 38–40 amino acids that bind proline-rich sequences in various proteins.
- COATED PIT
An invagination of the membrane involved in receptor-mediated endocytosis.
About this article
Cite this article
Herz, J., Beffert, U. Apolipoprotein E receptors: linking brain development and alzheimer's disease. Nat Rev Neurosci 1, 51–58 (2000). https://doi.org/10.1038/35036221
Neurochemical Research (2019)
How multi-scale structural biology elucidated context-dependent variability in ectodomain conformation along with the ligand capture and release cycle for LDLR family members
Biophysical Reviews (2018)
Increased Aβ42-α7-like nicotinic acetylcholine receptor complex level in lymphocytes is associated with apolipoprotein E4-driven Alzheimer’s disease pathogenesis
Alzheimer's Research & Therapy (2017)
Serum levels of apolipoprotein E correlates with disease progression and poor prognosis in breast cancer
Tumor Biology (2016)