Potential Biological Mechanisms of ApoE in Alzheimer’s Disease

  • G. William Rebeck
Part of the Contemporary Neuroscience book series (CNEURO)


Other chapters in this book discuss the three genes involved in the development of early onset forms of AD: APP, presenilin-1, and presenilin-2. These genes share a number of features. First, mutations in these genes lead to early onset-forms of AD. Second, mutations in these genes invariably lead to AD; i.e., they are completely penetrant. Third, the functions of the APP, presenilin-1, and presenilin-2 gene products are unknown. In order to determine the functions of these genes, considerable research is being invested in examining the distribution of these proteins, the regulation of their expression, and the identification of proteins that interact with them.


Neurite Outgrowth ApoE Genotype Human Apolipoprotein Macrophage Scavenger Receptor ApoE Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Louhija, J., Miettinen, H. E., Kontula, K., Tikkanen, M. J., Mietinen, T. A., and Tilvis, R. S. (1994) Aging and genetic variation of plasma apolipoproteins: relative loss of the apolipoprotein E4 phenotype in centenarians, Arteriosclerosis Thrombosis 14, 1084–1089.Google Scholar
  2. 2.
    Rebeck, G. W., Perls, T. T., West, H. L., Sodhi, P., Lipsitz, L. A., and Hyman, B. T. (1994) Reduced apolipoprotein E4 allele frequency in the oldest old Alzheimer’s patients and cognitively normal individuals, Neurology 44, 1513–1516.PubMedGoogle Scholar
  3. 3.
    Davignon, J., Gregg, R. E., and Sing, C. F. (1988) Apolipoprotein E polymorphism and atherosclerosis, Arteriosclerosis 8, 1–21.Google Scholar
  4. 4.
    Mahley, R. W. (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology, Science 240, 622–630.PubMedGoogle Scholar
  5. 5.
    Weisgraber, K. H. (1994) Apolipoprotein E:structure-function relationships, Advances in Protein Chemistry 45, 249–302.PubMedGoogle Scholar
  6. 6.
    Poduri, A., Gearing, M., Rebeck, G. W, Mirra, S. S., Tigges, J., and Hyman, B. T. (1994) Apolipoprotein E4 and beta amyloid in senile plaques and cerebral blood vessels of aged rhesus monkeys, Am. J. Pathol. 144, 1183–1187.PubMedGoogle Scholar
  7. 7.
    Zannis, V. I., Nicolosi, R. J., Jensen, E., Breslow, J. L., and Hayes, K. C. (1985) Plasma and hepatic ApoE isoproteins of nonhuman primates. Differences in apoE among humans, apes, and new and old world monkeys, J. Lipid Res. 26, 1421–1430.PubMedGoogle Scholar
  8. 8.
    Assmann, G. (1982) Lipid Metabolism and Atherosclerosis,E K. Schattauer, Stuttgart, Germany.Google Scholar
  9. 9.
    Segrest, J. P., Jones, M. K., De Loof, H., Brouillette, C. G., Venkatachalapathi, Y. V, and Anantharamaiah, G. M. (1992) The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function, J. Lipid Res. 33, 141–166.PubMedGoogle Scholar
  10. 10.
    Gregg, R. E., Zech, L.A., Schaefer, E. J., Stark, D., Wilson, D., and Brewer, H. B., Jr. (1986) Abnormal in vivo metabolism of apolipoprotein E4 in humans, J. Clin. Invest. 78, 815–821.PubMedGoogle Scholar
  11. 11.
    Weisgraber, K. H. (1990) Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine interchange at residue 112, J. Lipid Res. 31, 1503–1511.PubMedGoogle Scholar
  12. 12.
    Dong, L.-M., Wilson, C., Wardell, M. R., Simmons, T., Mahley, R. W., Weisgraber, K. H., and Agard, D. A. (1994) Human apolipoprotein E: role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms, J. Biol. Chem. 269, 22,358–22, 365.Google Scholar
  13. 13.
    Wilson, C., Wardell, M. R., Weisgraber, K. H., Mahley, R. W., and Agard, D. A. (1991) Three-dimensional structure of the LDL receptor binding domain of human apolipoprotein E, Science 252, 1817–1822.PubMedGoogle Scholar
  14. 14.
    Innerarity, T. L., Friedlander, E. J., Rall, S. C., Jr, Weisgraber, K. H., and Mahley, R. (1983) The receptor-binding domain of human apolipoprotein E, J. Biol. Chem. 258,12, 341–12, 347.Google Scholar
  15. 15.
    Lalazar, A., Weisgraber, K. H., Rall, S. C., Jr., Giladi, H., Innerarity, T. L., Levanon, A. Z., Boyles, J. K., Amit, B., Gorecki, M., Mahley, R. W., and Vogel, T. (1988) Site-specific mutagenesis of human apolipoprotein E: recptor binding activity of variants with single amino acid substitutions, J. Biol. Chem. 263, 3542–3545.PubMedGoogle Scholar
  16. 16.
    Weisgraber, K. H., Innerarity, T. L., Harder, K. J., Mahley, R. W., Milne, R. W., Marcel, Y. L., and Sparrow, J. T. (1983) The receptor-binding domain of human apolipoprotein E, J Biol. Chem. 258, 12,348–12, 354.Google Scholar
  17. 17.
    Kowal, R. C., Herz, J., Weisgraber, K. H., Mahley, R. W., Brown, M. S., and Goldstein, J. L. (1990) Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein, J. Biol. Chem. 265, 10,771–10, 779.Google Scholar
  18. 18.
    Weisgraber, K. H., Innerarity, T. L., and Mahley, R. W. (1982) Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site, J. Biol. Chem. 257, 2518–2521.PubMedGoogle Scholar
  19. 19.
    Weisgraber, K. H., and Mahley, R. W. (1978) Apoprotein (E-AII) complex of human plasma lipoproteins. I. Characterization of this mixed disulfide and its identification in a high density lipoprotein subfraction, J. Biol. Chem. 253, 6281–6288.PubMedGoogle Scholar
  20. 20.
    Tozuka, M., Hidaka, H., Miyachi, M., Furihata, K., Katsuyama, T., and Kanai, M. (1992) Identification and characterization of apolipoprotein (AII-E2-AII) complex in human plasma lipoprotein, Biochim. Biophys. Acta 1165, 61–67.PubMedGoogle Scholar
  21. 21.
    Borghini, I., James, R. W., Blatter, M.-C., and Pometta, D. (1991) Distribution of apolipoprotein E between free and A-II complexed forms in very-low-and high-density lipoproteins: functional implications, Biochim. Biophys. Acta. 1083, 139–146.PubMedGoogle Scholar
  22. 22.
    Innerarity, T. L., Mahley, R. W., Weisgraber, K. H., and Bersot, T. P. (1978) Apoprotein (E-AII) complex of human plasma lipoproteins. II. Receptor binding activity of a high density lipoprotein subtraction modulated by the apo(E-AII) complex, J. Biol. Chem. 253, 6289–6295.PubMedGoogle Scholar
  23. 23.
    Weisgraber, K. H. and Shinto, L. H. (1991) Identification of the disulfide-linked homodimer of apolipoprotein E3 in plasma. Impact on receptor binding activity, J. Biol. Chem. 266, 12,029–12, 034.Google Scholar
  24. 24.
    Yamamoto, T., Davis, C. G., Brown, M. S., Schneider, W. J., Casey, M. L., Goldstein, J. L., and Russell, D. W. (1984) The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA, Cell 39, 27–38.PubMedGoogle Scholar
  25. 25.
    Herz, J., Hamann, U., Rogne, S., Myklebost, O., Gausepohl, H., and Stanley, K. K. (1988) 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.PubMedGoogle Scholar
  26. 26.
    Strickland, D. K.,Ashcom, J. D., Williams, S., Burgess, W. H., Migliorini, M., andArgraves, W. S. (1990) Sequence identity between the a2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor, J. Biol. Chem. 265, 17, 401–17, 404.Google Scholar
  27. 27.
    Saito, A., Pietromonaco, S., Loo, A. K.-C., and Farquhar, M. G. (1994) 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.PubMedGoogle Scholar
  28. 28.
    Sakai, J., Hoshino, A., Takahashi, S., Miura, Y., Ishii, H., Suzuki, H., Kawarabayasi, Y., and Yamamoto, T. (1994) Structure, chromosome location, and expression of the human very low density lipoprotein receptor gene, J. Biol. Chem. 269, 2173–2182.PubMedGoogle Scholar
  29. 29.
    Kim, D.-H., lijima, H., Goto, K., Sakai, J., Ishii, H., Kim, H.-J., Suzuki, H., Kondo, H., Saeki, S., and Yamamoto, T. (1996) Human apolipoprotein E receptor 2, J. Biol. Chem. 271, 8373–8380.Google Scholar
  30. 30.
    Brown, M. S. and Goldstein, J. L. (1986) A receptor-mediated pathway for cholesterol homeostasis, Science 232, 34–47.PubMedGoogle Scholar
  31. 31.
    Borghini, I., Barja, F., Pometta, D., and James, R. W. (1995) Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid, Biochim. Biophys. Acta. 1255, 192–200.PubMedGoogle Scholar
  32. 32.
    Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., and Mahley, R. W. (1987) Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins, Biochim. Biophys. Acta 917, 148–161.Google Scholar
  33. 33.
    Pitas, R. E., Boyles, J. K., Lee, S. H., Hui, D., and Weisgraber, K. H. (1987) Lipoproteins and their receptors in the central nervous system, J Biol. Chem. 262, 14,352–14, 360.Google Scholar
  34. 34.
    Boyles, J. K., Pitas, R. E., Wilson, E., Mahley, R. W., and Taylor, J. M. (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system, J. Clin. Invest. 76, 1501–1513.PubMedGoogle Scholar
  35. 35.
    Poirier, J., Hess, M., May, P. C., and Finch, C. E. (1991) Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning, Mol. Brain Res. 11, 97–106.PubMedGoogle Scholar
  36. 36.
    Dyer, C. and Philibotte, T. (1995) A clone of the MOCH-1 glial tumor in culture: multiple phenotypes expressed under different environmental consitions, Neuropathol. Exp. Neurol. 54, 852–863.Google Scholar
  37. 37.
    Warnette-Hammond, M. E., Lauer, S. J., Corsini, A., Walker, D., Taylor, J. M., and Rall, Jr., S. C. (1989) Glycosylation of human apolipoprotein E. J. Biol. Chem. 264, 9094–9101.Google Scholar
  38. 38.
    Edmond, J., Korsak, R. A., Morrow, J. W., Torok-Both, G., and Catlin, D. H. (1991) Dietary cholesterol and the origin of cholesterol in the brain of developing rats, J Nutr. 121, 1323–1330.PubMedGoogle Scholar
  39. 39.
    Jurevics, H. and Morell, P. (1995) Cholesterol for synthesis of myelin is made locally, not imported into the brain, J. Neurochem. 64, 895–901.PubMedGoogle Scholar
  40. 40.
    Poirier, J., Baccichet, A., Dea, D., and Gauthier, S. (1993) Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats, Neuroscience 55, 81–90.PubMedGoogle Scholar
  41. 41.
    Goodrum, J. F. (1991) Cholesterol from degenerating nerve myelin becomes associated with lipoproteins containing apolipoprotein E, J. Neurochem. 56, 2082–2086.PubMedGoogle Scholar
  42. 42.
    Bellosta, S., Nathan, B. P., Orth, M., Dong, L.-M., Mahley, R. W., and Pitas, R. E. (1995) Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth, J. Biol. Chem. 270, 27,063–27, 071.Google Scholar
  43. 43.
    Rebeck, G. W., Reiter, J. S., Strickland, D. K., and Hyman, B. T. (1993) Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions, Neuron 11, 575–580.PubMedGoogle Scholar
  44. 44.
    Swanson, L. W., Simmons, D. M., Hofmann, S. L., Goldstein, J. L., and Brown, M. S. (1988) Localization of mRNA for low density lipoprotein receptor and a cholesterol synthetic enzyme in rabbit nervous system by in situ hybridization, Proc. Natl. Acad. Sci. USA 85, 9821–9825.PubMedGoogle Scholar
  45. 45.
    Bu, G., Maksymovitch, E. A., Nerbonne, J. M., and Schwartz, A. L. (1994) Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons, J. Biol. Chem. 269, 18,521–18, 528.Google Scholar
  46. 46.
    Moestrup, S. K., Gliemann, J., and Pallensen, G. (1992) Distribution of the a2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues, Cell Tissue Res. 269, 375–382.PubMedGoogle Scholar
  47. 47.
    Tooyama, I., Kawamata, T., Akiyama, H., Kimura, H., Moestrup, S. K., Gliemann, J., Matsuo, A., and McGeer, P. L. (1995) Subcellular localization of the low density lipoprotein receptor-related protein (a2-macroglobulin receptor) in human brain, Brain Res. 691, 235–238.PubMedGoogle Scholar
  48. 48.
    Wolf, B. B., Lopes, M. B. S., VandenBerg, S. R., and Gonias, S. L. (1992) Characterization and immunohistochemical localization of a2-macroglobulin receptor (low-density lipoprotein receptor-related protein) in human brain, Am. J. Pathol. 141, 37–42.PubMedGoogle Scholar
  49. 49.
    Zheng, G., Bachinsky, D. R., Stamenkovic, I., Strickland, D. K., Brown, D., Andres, G., and McCluskey, R. T. (1994) Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/a2MR, and the receptor-associated protein (RAP), J Histochem. Cytochem. 42, 531 - -542.PubMedGoogle Scholar
  50. 50.
    Christie, R. H., Chung, H., Rebeck, G. W., Strickland, D., and Hyman, B. T. (1996) Expression of the very low density lipoprotein receptor (VLDL-r), an apolipoprotein E receptor, in the central nervous system and in Alzheimer disease, J. Neuropath. Exp. Neurol. 55, 491–498.Google Scholar
  51. 51.
    Christie, R. H., Freeman, M., and Hyman, B. T. (1996) Expression of the macrophage scavenger receptor, a multifunctional lipoprotein receptor, in microglia associated with senile plaques in Alzheimer’s disease, Am. J. Pathol. 148, 399–403.Google Scholar
  52. 52.
    Okuizumi, K., Onodera, O., Namba, Y., Ikeda, K., Yamamoto, T., Seki, K., Ueki, A., Nanko, S., Tanaka, H., Takahashi, H., Oyanagi, K., Mizusawa, H., Kanazawa, I., and Tsuji, S. (1995) Genetic association of the very low density lipoprotein (VLDL) receptor with sporadic Alzheimer’s disease, Nature Genet. 11, 207–209.PubMedGoogle Scholar
  53. 53.
    Krieger, M. and Herz, J. (1994) Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP), Ann. Rev. Biochem. 63, 601–37.PubMedGoogle Scholar
  54. 54.
    Snipes, G. J., McGuire, C. B., Norden, J. J., and Freeman, J. A. (1986) Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells, Proc. Natl. Acad. Sci. USA 83, 1130–1134.Google Scholar
  55. 55.
    Masliah, E., Mallory, M., Ge, N., Alford, M., Veinbergs, I., and Roses, A. D. (1995) Neurodegeneration in the central nervous system of apoE-deficient mice, Exp. Neurol. 136, 107–122.PubMedGoogle Scholar
  56. 56.
    Handelmann, G. E., Boyles, J. K., Weisgraber, K. H., Mahley, R. W., and Pitas, R. E. (1992) Effects of apolipoprotein E, (3-very low density lipoproteins, and cholesterol on the extensions of neurites by rabbit dorsal root ganglion neurons in vitro, J. Lipid Res. 33, 1677–1688.PubMedGoogle Scholar
  57. 57.
    Holtzman, D. M., Pitas, R. E., Kilbridge, J., Nathan, B., Mahley, R. W., Bu, G., and Schwartz, A. L. (1995) 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.PubMedGoogle Scholar
  58. 58.
    Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E., and Ikeda, K. (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease, Brain Res. 541, 163–166.PubMedGoogle Scholar
  59. 59.
    Nathan, B. P., Bellosta, S., Sanan, D. A., Weisgraber, K. H., Mahley, R. W., and Pitas, R. E. (1994) Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro, Science 264, 850–852.PubMedGoogle Scholar
  60. 60.
    Arai, H., Muramatsu, T., Higuchi, S., Sasaki, H., and Trojanowski, J. Q. (1994) Apolipoprotein E gene in Parkinson’s disease with or without dementia, Lancet 344, 889.PubMedGoogle Scholar
  61. 61.
    Benjamin, R., Leake, A., Edwardson, J. A., McKeith, I. G., Ince, P. G., Perry, R. H., and Morris, C. M. (1994) Apolipoprotein E genes in Lewy body and Parkinson’s disease, Lancet 343, 1565.PubMedGoogle Scholar
  62. 62.
    Koller, W. C., Glatt, S. L., Hubble, J. P., Paolo, A., Troster, A. I., Handler, M. S., Horvat, R. T., Martin, C., Schmidt, K., Karst, A., Wijsman, E. M., Yu, C.-E., and Schellenberg, G. D. (1995) Apolipoprotein E genotypes in Parkinson’s disease with and without dementia, Ann. Neurol. 37, 242–245.PubMedGoogle Scholar
  63. 63.
    Mui, S., Rebeck, G. W., McKenna-Yasek, D., Hyman, B. T., and Brown, R. H. (1995) Apolipoprotein E e4 allele is not associated with earlier age at onset in amyotrophic lateral sclerosis, Ann. Neurol. 380, 460 X63.Google Scholar
  64. 64.
    Nakagawa, Y., Kitamoto, T., Furukawa, H., Ogomori, K., and Tateishi, J. (1995) Apolipoprotein E in Creutzfeldt-Jakob disease, Lancet 345, 68.Google Scholar
  65. 65.
    Pickering-Brown, S. M., Mann, D. M.A., Owen, F., Ironside, J. W., de Silva, R., Roberts, D. A., Balderson, D. J., and Cooper, P. N. (1995) Allelic variation in apolipoprotein E and prion protein genotype related to plaque formation and age of onset in sporadic Creutzfeld-Jakob disease, Neurosci. Lett. 187, 127–129.PubMedGoogle Scholar
  66. 66.
    Roses, A. D., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Pericak-Vance, M. A., and Hyman, B. (1995) Apolipoprotein E in Creutzfeldt-Jakob disease, Lancet 345, 69.Google Scholar
  67. 67.
    Saunders, A. M., Schmader, K., Breitner, J. C. S., Benson, M. D., Brown, W. T., Goldfarb, L., Goldgaber, D., Manworing, M. G., Szymanski, M. H., McCown, N., Dole, K. C., Schmechel, D. E., Strittmatter, W. J., Pericak-Vance, M. A., and Roses, A. D. (1993) Apolipoprotein E e4 allele distributions in late-onset Alzheimer’s disease and in other amyloid-forming diseases, Lancet 342, 710–711.PubMedGoogle Scholar
  68. 68.
    Zerr, I., Helmhold, M., and Weber, T. (1995) Apolipoprotein E in Creutzfeldt-Jakob disease, Lancet 345, 68, 69.Google Scholar
  69. 69.
    Gomez-Isla, T., West, H. L., Rebeck, G. W., Harr, S. D., Growdon, J. H., Locasio, J. J., Perls, T. T., Lipsitz, L. A., and Hyman, B. T. (1996) Clinical and pathological correlates of apolipoprotein E e4 in Alzheimer disease, Ann. Neurol. 39, 62–70.Google Scholar
  70. 70.
    Al-Chalabi, A., Enayat, Z. E., Bakker, M. C., Sham, P. C., Ball, D. M., Shaw, C. E., Lloyd, C. M., Powell, J. F., and Leigh, P. N. (1996) Association of apolipoprotein E e4 with bulbar onset motor neuron disease, Lancet 347, 159, 160.Google Scholar
  71. 71.
    Gearing, M., Schneider, J. A., Rebeck, G. W., Hyman, B. T., and Mirra, S. S. (1995) Alzheimer’s disease with and without coexisting Parkinson’s disease changes: apolipoprotein E genotype and neuropathological correlates, Neurology 45, 1985–1990.Google Scholar
  72. 72.
    Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B., Hulette, C., Joo, S. H., Pericak-Vance, M. A., Goldgaber, D., and Roses, A. D. (1993) Increased amyloid 13-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimers disease, Proc. Natl. Acad. Sci. USA 90, 9649–9653.Google Scholar
  73. 73.
    Nagy, Z. S., Esiri, M. M., Jobst, K. A., Johnston, C., Litchfield, S., Sim, E., and Smith, A. D. (1995) Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer’s disease, Neuroscience 69, 757–761.PubMedGoogle Scholar
  74. 74.
    Ohm, T. G., Kirca, M., Bohl, J., Scharnagl, H., Gross, W., and Marz, W. (1995) Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation, Neuroscience 66, 583–587.PubMedGoogle Scholar
  75. 75.
    Polvikoski, T., Sulkava, R., Haltia, M., Kainulainen, K., Vuorio, A., Verkkoniemi, A., Niinisto, L., Halonen, P., and Kontula, K. (1995) Apolipoprotein E, dementia, and cortical deposition of f3-amyloid protein, N. Engl. J. Med. 333, 1242–1247.PubMedGoogle Scholar
  76. 76.
    Strittmatter, W. J., Saunders, A. M., Goedert, M., Weisgraber, K. H., Dong, L.-M., Jakes, R., Huang, D. Y., Pericak-Vance, M., Schmechel, D., and Roses, A. D. (1994) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease, Proc. Natl. Acad. Sci. USA 91, 11,183–11, 186.Google Scholar
  77. 77.
    Han, S.-H., Einstein, G., Weisgraber, K. H., Strittmatter, W. J., Saunders, A. M., PericakVance, M., Roses, A. D., and Schmechel, D. E. (1994) Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study, J. Neuropathol. Exp. Neurol. 53, 535–544.PubMedGoogle Scholar
  78. 78.
    Han, S.-H., Hulette, C., Saunders, A. M., Einstein, G., Pericak-Vance, M., Strittmatter, W. J., Roses, A. D., and Schmechel, A. E. (1994) Apolipoprotein E is present in hippocampal neurons without neurofibrillary tangles in Alzheimer’s disease and in age-matched controls, Exp. Neurol. 128, 13–26.PubMedGoogle Scholar
  79. 79.
    Hamilton, R. L., Wong, J. S., Guo, L. S. S., Krisans, S., and Havel, R. J. (1990) Apolipoprotein E localization in rat hepatocytes by immunogold labeling of cyrothin sections, J. Lipid Res. 31, 1589–1603.PubMedGoogle Scholar
  80. 80.
    Metzger, R. E., LaDu, M. J., Pan, J. B., Getz, G. S., Frail, D. E., and Falduto, M. T. (1996) Neurons of the human frontal cortex display apolipoprotein E immunoreactivity: implications for Alzheimer’s disease, J. Neuropathol. Exp. Neurol. 55, 372–380.Google Scholar
  81. 81.
    Genis, I., Gordon, I., Sehayek, E., and Michaelson, D. M. (1995) Phosphorylation of tau in apolipoprotein E-deficient mice, Neurosci. Lett. 199, 5–8.PubMedGoogle Scholar
  82. 82.
    Nathan, B. P., Chang, K.-C., Bellosta, S., Brisch, E., Ge, N., Mahley, R. W., and Pitas, R. E. (1995) The inhibitory effect of apolipoprotein E4 on neurite outgrowth is associated with microtubule depolymerization, J. Biol. Chem. 370, 19,791–19, 799.Google Scholar
  83. 83.
    Wisniewski, T., and Frangione, B. (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid, Neurosci. Lett. 135, 235–238.PubMedGoogle Scholar
  84. 84.
    Greenberg, S. M., Rebeck, G. W., Vonsattel, J. P. G., Gomez-Isla, T., and Hyman, B. (1995) Apolipoprotein E e4 and cerebral hemorrhage associated with amyloid angiopathy, Ann. Neurol. 38, 254–259.Google Scholar
  85. 85.
    Nicoll, J. A. R., Roberts, G. W., and Graham, D. I. (1995) Apolipoprotein E4 allele is associated with deposition of amyloid B-protein following head injury, Nature Med. 1, 135–137.PubMedGoogle Scholar
  86. 86.
    Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., and Pericak-Vance, M. A. (1993) Gene dose of apolipoprotein E type 4 allele and the risk ofAlzheimer’s disease in late onset families, Science 261, 921–923.PubMedGoogle Scholar
  87. 87.
    Tsai, M.-S., Tangalos, E. G., Petersen, R. C., Smith, G. E., Schaid, D. J., Kokmen, E., Ivnek, R. J., and Thibodeau, N. (1994) Apoliprotein E: risk factor for Alzheimer’s disease, Am. J. Hum. Genet. 54, 643–649.PubMedGoogle Scholar
  88. 88.
    Hardy, J. and Allsop, D. (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease, Trends Pharmacol. Sci. 12, 383–388.PubMedGoogle Scholar
  89. 89.
    Mann, D. M. A., Marcyniuk, B., Yates, P. 0., Neary, D., and Snowden, J. S. (1988) The progression of the pathological changes of Alzheimer’s disease in frontal and temporal neocortex examined at both biopsy and autopsy, Neuropathol. Appl. Neurobiol. 14, 177–195.Google Scholar
  90. 90.
    Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., and Roses, A. D. (1993) Apolipoprotein E: high-avidity binding to 0-amyloid and increased frequence of type 4 allele in late-onset familial Alzheimer disease, Proc. Natl. Acad. Sci. USA 90, 1977–1981.PubMedGoogle Scholar
  91. 91.
    Strittmatter, W. J., Weisgraber, K. H., Huang, D., Dong, L. M., Salvesen, G. S., PericakVance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., and Roses, A. D. (1993) Binding of human apolipoprotein E to 13A4 peptide: isoform specific effects and impications for late onset Alzheimer disease, Proc. Natl. Acad. Sci. USA 90, 8098–8102.PubMedGoogle Scholar
  92. 92.
    LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S., and Frail, D. E. (1994) Isoform-specific binding of apolipoprotein E to 13-amyloid,./ Biol. Chem. 269, 23,40323, 406.Google Scholar
  93. 93.
    LaDu, M. J., Pederson, T. M., Frail, D. E., Reardon, C. A., Getz, G., and Falduto, M. T. (1995) Purification of apolipoprotein E attenuates isoform-specific binding to f3-amyloid, J. Biol. Chem. 270, 9039–9042.PubMedGoogle Scholar
  94. 94.
    Zhou, Z., Smith, J. D., Greengard, P., and Gandy, S. (1996) Alzheimer amyloid-13 peptide forms denaturant-resistant complex with type E3 but not type E4 isoform of apolipoprotein E, Mol. Med. 2, 175–180.PubMedGoogle Scholar
  95. 95.
    Koudinov, A., Matsubara, E., Frangione, B., and Ghiso, J. (1994) The soluble form of Alzheimer’s amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma, Biochem. Biophys. Res. Commun. 205, 1164–1171.PubMedGoogle Scholar
  96. 96.
    Yanagisawa, K., Odaka, A., Suzuki, N., and Ihara, Y. (1995) GM1 ganglioside-bound amyloid 13-protein (A13): a possible form of preamyloid in Alzheimer’s disease, Nature Med. 1, 1062–1066.PubMedGoogle Scholar
  97. 97.
    Tooyama, I., Kawamata, T., Akiyama, H., Moestrup, S. K., Gliemann, J., and McGeer, P. L. (1993) Immunohistochemical study of a2 macroglobulin receptor in Alzheimer and control postmortem human brain, Mol. Chem. Neuropathol. 18, 153–160.PubMedGoogle Scholar
  98. 97a.
    Kowal, R. C., Herz, J., Goldstein, J. L., Esser, V., and Brown, M. S. (1989) Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins, Proc. Natl. Acad. Sci. USA 86, 5810–5814.PubMedGoogle Scholar
  99. 98.
    Beisiegel, U., Weber, W., Ihrke, G., Herz, J., and Stanley, K. K. (1989) The LDL-receptorrelated protein, LRP, is an apolipoprotein E-binding protein, Nature 341, 162–164.PubMedGoogle Scholar
  100. 99.
    Beisiegel, U., Weber, W., and Bengtsson-Olivecrona, G. (1991) Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein, Proc. Natl. Acad. Sci. USA 88, 8342–8346.PubMedGoogle Scholar
  101. 100.
    Kounnas, M. Z., Chappell, D. A., Wong, H., Argraves, W. S., and Strickland, D. K. (1995) The cellular internalization and degradation of hepatic lipase is mediated by low density lipoprotein receptor-related protein and requires cell surface proteoglycans, J Biol. Chem. 270, 9307–9312.PubMedGoogle Scholar
  102. 101.
    Kounnas, M. Z., Moir, R. D., Rebeck, G. W., Bush, A. I., Argraves, W. S., Tanzi, R. E., Hyman, B. T., and Strickland, D. K. (1995) LDL receptor-related protein, a multifunctional apoE receptor, binds secreted 13-amyloid precursor protein and mediates its degradation, Cell 82, 331–340.PubMedGoogle Scholar
  103. 102.
    Bu, G., Williams, S., Strickland, D. K., and Schwartz, A. L. (1992) Low density lipoprotein receptor-related protein/a2-macroglobulin receptor is a hepatic receptor for tissue-type plasminogen activator, Proc. Natl. Acad. Sci. USA 89, 7427–7431.PubMedGoogle Scholar
  104. 103.
    Kounnas, M. Z., Henkin, J., Argraves, W. S., and Strickland, D. K. (1993) Low density lipoprotein receptor-related protein/a2-macroglobulin receptor mediates cellular uptake of pro-urokinase, J. Biol. Chem. 268, 21,862–21, 867.Google Scholar
  105. 104.
    Nykjaer, A., Petersen, C. M., Moeller, B., Jensen, P. H., Moestrup, S., Holtet, T. L., Etzerodt, M., Thorgersen, H. C., Munch, M., Andreasen, P. A., and Gliemann, J. (1992) Purified a2macroglobulin receptor/LDL receptor-related protein binds urokinase-plasminogen activator inhibitor type-1 complex, J. Biol. Chem. 267, 14,543–14, 546.Google Scholar
  106. 105.
    Orth, K., Madison, E. L., Gething, M.-J., Sambrook, J. F., and 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/a2macroglobulin receptor, Proc. Natl. Acad. Sci. USA 89, 7422–7426.PubMedGoogle Scholar
  107. 106.
    Warshawsky, I., Broze, G. J., Jr, and Schwartz, A. L. (1994) The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor, Proc. Natl. Acad. Sci. USA 91, 6664–6668.PubMedGoogle Scholar
  108. 107.
    Willnow, T. E., Goldstein, J. L., Orth, K., Brown, M. S., and Herz, J. (1992) Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance, J. Biol. Chem. 267, 26,172–26, 180.Google Scholar
  109. 108.
    Mikhailenko, I., Kounnas, M. Z., and Strickland, D. K. (1995) Low density lipoprotein receptor-related protein/a2-macroglobulin receptor mediates the cellular internalization and degradation of thrombospondin, J. Biol. Chem. 270, 9543–9549.PubMedGoogle Scholar
  110. 109.
    Kounnas, M. Z., Morris, R. E., Thompson, M. R., FitzGerald, D. J., Strickland, D. K., and Saelinger, C. B. (1992) The a2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A, J. Biol. Chem. 267, 12,420–12, 423.Google Scholar
  111. 110.
    Bauer, J., Strauss, S., Schreiter-Gasser, U., Ganter, U., Schlegel, P., Witt, I., Yolk, B., and Berger, M. (1991) Interleukin-6 and a2-macroglobulin indicate an acute-phase state in ALzheimer’s disease cortices, FEBS Lett. 285, 111–114.PubMedGoogle Scholar
  112. 111.
    Buee, L., Hof, P. R., Roberts, D. D., Delacourte, A., Morrison, J. H., and Fillit, H. M. (1992) Immunohistochemical identification of thrombospondin in normal human brain and in Alzheimer’s disease, Am. J Pathol. 141, 783–788.PubMedGoogle Scholar
  113. 112.
    Hollister, R. D., Kisiel, W., and Hyman, B. T. (1996) Immunohistochemical localization of tissue factor pathway inhibitor-1 (TFPI-1), a kunitz proteinase inhibitor, in Alzheimer’s disease, Brain Res. in press.Google Scholar
  114. 113.
    Kawamata, T., Tooyama, I., Yamada, T., Walker, D. G., and McGeer, P. L. (1993) Lactotransferrin immunocytochemistry in Alzheimer and normal human brain, Am. J. Pathol. 142, 1574–1585.PubMedGoogle Scholar
  115. 114.
    van Gool, D., de Strooper, B., van Leuven, F., Triau, E., and Dom, R. (1993) a2-Macroglobulin expression in neuritic-type plaques in patients with Alzheimer’s disease, Neurobiol. Aging 14, 233–237.Google Scholar
  116. 115.
    Nitsch, R. M., Blusztajn, J. K., Pittas, A. G., Slack, B. E., Growdon, J. H., and Wurtman, R. J. (1992) Evidence for a membrane defect in Alzheimer disease brain, Proc. Natl. Acad. Sci. USA 89, 1671–1675.PubMedGoogle Scholar
  117. 116.
    Soderberg, M., Edlund, C., Alafuzoff, I., Kristensson, K., and Dallner, G. (1992) Lipid composition in different regions of the brain in Alzheimer’s disease/senile dementia of Alzheimer’s type, J. Neurochem. 59, 1646–1653.PubMedGoogle Scholar
  118. 117.
    Svennerholm, L., and Gottfries, C.-G. (1994) Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late onset form (type II), J. Neurochem. 62, 1039–1047.PubMedGoogle Scholar
  119. 118.
    Castano, E. M., Prelli, F., Wisniewski, T., Golabek, A., Kumar, R. A., Soto, C., and Frangione, B. (1995) Fibrillogenesis in Alzheimer’s disease of amyloid 3 peptides and apolipoprotein E, Biochem. J. 306, 599 - -604.PubMedGoogle Scholar
  120. 119.
    Ma, J., Yee, A., Brewer, A. Y. H., Jr., Das, S., and Potter, H. (1994) Amyloid-associated proteins al-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer 13-protein into filaments, Nature 372, 92–94.Google Scholar
  121. 120.
    Sanan, D. A., Weisgraber, K. H., Russell, S. J., Mahley, R. W., Huang, D., Saunders, A., Schmechel, D., Wisniewski, T., Frangione, B., Roses, A., and Strittmatter, W. J. (1994) Apolipoprotein E associates with 13-amyloid peptide of Alzheimer’s disease to form novel monofibrils, J. Clin. Invest. 94, 860–869.PubMedGoogle Scholar
  122. 121.
    Wisniewski, T., Castano, E. M., Golabek, A., Vogel, T., and Frangione, B. (1994) Acceleration of Alzheimer’s disease fibril formation by apolipoprotein E in vitro, Am. J Pathol. 145, 1030–1035.Google Scholar
  123. 122.
    Evans, K. C., Berger, E. P., Cho, C.-G., Weisgraber, K. H., and Lansbury, P. T. (1995) Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease, Proc. Natl. Acad. Sci. USA 92, 763–767.PubMedGoogle Scholar
  124. 123.
    Terzi, E., Holzemann, G., and Seelig, J. (1995) Self-association of ß-amyloid peptide (1–40) in solution and binding to lipid membranes, J. Mol. Biol. 252, 633–642.PubMedGoogle Scholar
  125. 124.
    Bodovitz, S. and Klein, W. L. (1996) Cholesterol modulates a-secretase cleavage of amyloid precursor protein, J. Biol. Chem. 271, 4436–4440.PubMedGoogle Scholar
  126. 125.
    Nitsch, R. M., Rebeck, G. W., Deng, M., Richardson, U. I., Tennis, M., Schenk, D. B., VigoPelfrey, C., Lieberburg, I., Wurtman, R. J., Hyman, B. T., and Growdon, J. H. (1995) Cerebrospinal fluid levels of amyloid P.-protein in Alzheimer’s disease: inverse correlation with severity of dementia and effect of apoE genotype, Ann. Neurol. 37, 512–518.PubMedGoogle Scholar

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© Springer Science+Business Media New York 1997

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  • G. William Rebeck

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