ApoE Receptors in the Brain: Novel Signaling Pathways with Potential Relevance for Alzheimer’s Disease
Apolipoprotein E (ApoE) is an intrinsic component of lipoproteins and is known to transport cholesterol and other lipids through the circulation and between cells. ApoE binds to a family of cell surface receptors, the LDL receptor gene family. This class of endocytic receptors mediates the internalization of the lipoprotein particle, followed by transport of the lipids to the lysosomes. Several years ago, one isoform of ApoE, ApoE4, was reported to be genetically associated with late-onset Alzheimer’s disease. The biochemical mechanism by which ApoE4 predisposes its carriers to this debilitating neurodegenerative condition remains largely an enigma. We have investigated whether ApoE receptors on neurons are involved in the molecular pathogenic process. LRP, a member of the LDL receptor gene family, binds the amyloid precursor protein (APP) on its extracellular domain and is also connected to the cytoplasmic tail of APP by the adaptor protein FE65. This two-point interaction suggests that LRP may affect the subcellular localization, routing, and possibly processing of APP. Recently, we also described a novel signaling pathway by which two other members of the family, the VLDL receptor and the ApoE receptor 2, serve to transmit a positional cue across the membrane to migrating neurons. The signaling molecule, Reelin, binds to the receptor ectodomains and induces tyrosine phosphorylation of the intracellular adaptor protein Disabled-1. Disruption of this ApoE receptor-mediated signal transduction pathway results in hyperphosphorylation of the microtubule stabilizing protein tau, a prerequisite for the formation of neurofibrillary tangles in humans afflicted with Alzheimer’s disease. These findings tie neuronal ApoE receptors directly to two of the prominent pathological changes that are diagnostic for the disease: amyloid plaques, caused by abnormal processing of APP, and neurofibrillary tangles, caused by hyperphosphorylation of tau. We conclude that ApoE receptors regulate essential cellular signaling pathways in neurons and that defects in these pathways may accelerate the onset of Alzheimer’s disease.
KeywordsCholesterol Migration Tyrosine Recombination Peri
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- Kim DH, Iijima H, Goto K, Sakai J, Ishii H, Kim HJ, Suzuki H, Kondo H, Saeki S, Yamamoto T (1996) Human apolipoprotein E receptor 2. A novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in the brain. J Biol Chem 271: 8373–8380Google Scholar
- Krieger M, Herz J (1994) Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein ( LRP ). Ann Rev Biochem 63: 601–637Google Scholar
- Mac Lachlan I, Nimpf J, Schneider WJ (1994) Avian riboflavin binding protein binds to lipoprotein receptors in association with vitellogenin. J Biol Chem 269: 24127–24132Google Scholar
- Novak S, Hiesberger T, Schneider WJ, Nimpf J (1996) A new low density lipoprotein receptor homologue with 8 ligand binding repeats in brain of chicken and mouse (published erratum appears in J Biol Chem 1996 Oct 25, 271(43): 27188). J Biol Chem 271: 11732–11736Google Scholar
- Nykjaer A, Petersen CM, Moller B, Jensen PA, Moestrup SK, Holtet TL, Etzerodt M, Thogersen HC, Munch M, Andreasen PA, Gliemann J (1992) Purified a2-macroglobulin receptor/LDL receptor-related protein binds urokinase:plasminogen activator inhibitor type-1 complex. J Biol Chem 267: 14543–14546PubMedGoogle Scholar
- Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna Pant HC, Brady RO, Martin LJ, Kulkarni AB (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci USA 93: 11173–11178PubMedCrossRefGoogle Scholar
- Orth K, Madison EL, Gething MJ, Sambrook JF, Herz J (1992) Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. Proc Natl Acad Sci USA 89: 7422–7426PubMedCrossRefGoogle Scholar
- Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer’s disease. Proc Natl Acad Sci USA 90: 9649–9653CrossRefGoogle Scholar
- Trommsdorff M, Borg JP, Margolis B, Herz J (1998) Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein. J Biol Chem 273: 33556–33560Google Scholar
- Webb DJ, Nguyen DH, Gonias SL (2000) Extracellular signal-regulated kinase functions in the urokinase receptor-dependent pathway by which neutralization of low density lipoprotein receptor-related protein promotes fibrosarcoma cell migration and matrigel invasion (in process citation). J Cell Sci 113: 123–134PubMedGoogle Scholar
- Yochem J, Greenwald I (1993) A gene for a low density lipoprotein receptor-related protein in the nematode Caenorhabditis elegans. J Biol Chem 268: 13002–13009Google Scholar