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Closing in on the amyloid cascade

Recent insights into the cell biology of Alzheimer’s disease

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Abstract

Accumulation of the amyloid-β (Aβ) peptide in the central nervous system (CNS) is considered by many to be the crucial pathological insult that ultimately leads to the development of Alzheimer’s disease (AD). Regulating the production and/or aggregation of Aβ could therefore be of considerable benefit to patients afflicted with AD. It has long been known that Aβ is derived from the proteolytic processing of the amyloid precursor protein (APP) by two enzymatic activities, β-secretase and γ-secretase. Recent breakthroughs have led to the identification of the aspartyl protease BACE (β-site APP-cleaving enzyme) as β-secretase and the probable identification of the presenilin proteins as γ-secretases. This review discusses what is know about BACE and the presenilins, focusing on their capacity as secretases, as well as the options for therapeutic advancement the careful characterization of these proteins will provide. These findings are presented in the context of the “amyloid cascade hypothesis” and its physiological relevance in AD pathogenesis.

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References

  1. Selkoe D. J. (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399(Suppl.), A23-A31.

    PubMed  CAS  Google Scholar 

  2. Glenner G. G. and Wong C. W. (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Comm. 120, 885–890.

    PubMed  CAS  Google Scholar 

  3. Roher A. E., Lowenson J. D., Clarke S, Wolkow C, Wang R, Cotter R. J., et al. (1993) Structural alterations in the peptide backbone of β-amyloid core protein may account for its deposition and stability in Alzheimer’s disease. J. Biol. Chem. 268, 3072–3083.

    PubMed  CAS  Google Scholar 

  4. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, and Ihara Y. (1994) Visualization of Aβ 42(43) and Aβ 40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ 42(43). Neuron 13, 45–53.

    PubMed  CAS  Google Scholar 

  5. Barrow C. J. and Zagorski M. G. (1991) Solution structures of β peptide and its constituent fragments: relation to amyloid deposition. Science 253, 179–182.

    PubMed  CAS  Google Scholar 

  6. Jarrett J. T., Berger E. P., and Lansbury P. T., Jr. (1993) The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32, 4693–4697.

    PubMed  CAS  Google Scholar 

  7. Pike C. J., Overman M. J., and Cotman C. W. (1995) Amino-terminal deletions enhance aggregation of β-amyloid peptides in vitro. J. Biol. Chem. 270, 23,895–23,898.

    CAS  Google Scholar 

  8. Kang D. E., Soriano S, Frosch M. P., Collins T, Naruse S, Sisodia S. S., et al. (1999) Presenilin 1 facilitates the constitutive turnover of β-catenin: differential activity of Alzheimer’s disease-linked PS1 mutants in the β-cateninsignaling pathway. J. Neurosci. 19, 4229–4237.

    PubMed  CAS  Google Scholar 

  9. Selkoe D. J. (1994) Cell biology of the amyloid β-protein precursor and the mechanism of Alzheimer’s disease. Ann. Rev. Cell Biol. 10, 373–403.

    PubMed  CAS  Google Scholar 

  10. Schubert D, Jin L. W., Saitoh T, and Cole G. (1989) The regulation of amyloid β protein precursor secretion and its modulatory role in cell adhesion. Neuron 3, 689–694.

    PubMed  CAS  Google Scholar 

  11. Klier F. G., Cole G, Stallcup W., and Schubert D. (1990) Amyloid β-protein precursor is associated with extracellular matrix. Brain Res. 515, 336–342.

    PubMed  CAS  Google Scholar 

  12. Breen K. C., Bruce M., and Anderton B. H. (1991) β amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion. J. Neurosci. Res. 28, 90–100.

    PubMed  CAS  Google Scholar 

  13. Chen M. and Yankner B. A. (1991) An antibody to β amyloid and the amyloid precursor protein inhibits cell-substratum adhesion in many mammalian cell types. Neurosci. Lett. 125, 223–226.

    PubMed  CAS  Google Scholar 

  14. Small D. H., Nurcombe V., Reed G., Clarris H., Moir R., Beyreuther K, and Masters C. L. (1994) A heparin-binding domain in the amyloid protein precursor of Alzheimer’s disease is involved in the regulation of neurite outgrowth. J. Neurosci. 14, 2117–2127.

    PubMed  CAS  Google Scholar 

  15. Milward E. A., Papadopoulos R., Fuller S. J., Moir R. D., Small D., Beyreuther K., and Masters C. L. (1992) The amyloid protein precursor of Alzheimer’s disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron 9, 129–137.

    PubMed  CAS  Google Scholar 

  16. Qiu W. Q., Ferreira A., Miller C., Koo E. H., and Selkoe D. J. (1995) Cell-surface β-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J. Neurosci. 15, 2157–2167.

    PubMed  CAS  Google Scholar 

  17. Perez R. G., Zheng H., Van der Ploeg L. H., and Koo E. H. (1997) The β-amyloid precursor protein of Alzheimer’s disease enhances neuron viability and modulates neuronal polarity. J. Neurosci. 17, 9407–9414.

    PubMed  CAS  Google Scholar 

  18. Mattson M. P., Cheng B., Culwell A. R., Esch F. S., Lieberburg I., and Rydel R. E. (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein. Neuron 10, 243–254.

    PubMed  CAS  Google Scholar 

  19. Saitoh T., Sundsmo M., Roch J. M., Kimura N, Cole G., Schubert D., et al. (1989) Secreted form of amyloid β protein precursor is involved in the growth regulation of fibroblasts. Cell 58, 615–622.

    PubMed  CAS  Google Scholar 

  20. Pietrzik C. U., Hoffmann J., Stober K., Chen C. Y., Bauer C., Otero D. A., et al. (1998) From differentiation to proliferation: the secretory amyloid precursor protein as a local mediator of growth in thyroid epithelial cells. Proc. Natl. Acad. Sci. USA 95, 1770–1775.

    PubMed  CAS  Google Scholar 

  21. Zheng H., Jiang M., Trumbauer M. E., Sirinathsinghji D. J., Hopkins R., Smith D. W., et al. (1995) β-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81, 525–531.

    PubMed  CAS  Google Scholar 

  22. Oltersdorf T, Fritz L. C., Schenk D. B., Lieberburg I, Johnson-Wood K. L., Beattie E. C., et al. (1989) The secreted form of the Alzheimer’s amyloid precursor protein with the Kunitz domain in protease nexin-II. Nature 341, 144–147.

    PubMed  CAS  Google Scholar 

  23. Van Nostrand W. E., Wagner S. L., Suzuki M., Choi B. H., Farrow J. S., Geddes J. W., et al. (1989) Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid β-protein precursor. Nature 341, 546–549.

    PubMed  Google Scholar 

  24. Sinha S., Dovey H. F., Seubert P., Ward P. J., Blacher R. W., Blaber M., et al. (1990) The protease inhibitory properties of the Alzheimer’s β-amyloid precursor protein. J. Biol. Chem. 265, 8983–8985.

    PubMed  CAS  Google Scholar 

  25. Haass C., Schlossmacher M. G., Hung A. Y., Vigo-Pelfrey C., Mellon A., Ostaszewski B. L., et al. (1992) Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359, 322–325.

    PubMed  CAS  Google Scholar 

  26. Shoji M., Golde T. E., Ghiso J., Cheung T. T., Estus S., Shaffer L. M., et al. (1992) Production of the Alzheimer amyloid β protein by normal proteolytic processing. Science 258, 126–129.

    PubMed  CAS  Google Scholar 

  27. Seubert P., Vigo-Pelfrey C., Esch F., Lee M., Dovey H., Davis D., et al. (1992) Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature 359, 325–327.

    PubMed  CAS  Google Scholar 

  28. Haass C., Koo E. H., Mellon A., Hung A. Y., and Selkoe D. J. (1992) Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid bearing fragments. Nature 357, 500–503.

    PubMed  CAS  Google Scholar 

  29. Koo E. H. and Squazzo S. L. (1994) Evidence that production and release of amyloid β-protein involves the endocytic pathway. J. Biol. Chem. 269, 17,386–17,389.

    CAS  Google Scholar 

  30. Haass C., Lemere C. A., Capell A., Citron M., Seubert P., Schenk D., et al. (1995) The Swedish mutation causes early-onset Alzheimer’s disease by β-secretase cleavage within the secretory pathway. Nat. Med. 1, 1291–1296.

    PubMed  CAS  Google Scholar 

  31. Thinakaran G., Teplow D. B., Siman R., Greenberg B., and Sisodia S. S. (1996) Metabolism of the “Swedish” amyloid precursor protein variant in neuro2a (N2a) cells. J. Biol. Chem. 271, 9390–9397.

    Google Scholar 

  32. Xu H., Sweeny D., Wang R., Thinakaran G., Lo A. C. Y., Sisodia S. S., et al. (1997) Generation of Alzheimer β-amyloid protein in the transgolgi network in the apparent absence of vescicle formation. Proc. Natl. Acad. Sci. USA 94, 3748–3752.

    PubMed  CAS  Google Scholar 

  33. Chyung A. S. C., Greenberg B. D., Cook D. G., Doms R. W., and Lee V. M.-Y. (1997) Novel β-secretase cleavage of β-amyloid precursor protein in the endoplasmic reticulum/intermediate compartment of NT2N cells. J. Cell. Biol. 138, 671–680.

    PubMed  CAS  Google Scholar 

  34. Cook D. G., Forman M. S., Sung J. C., Leight S., Kolson D. L., Iwatsubo T., et al. (1997) Alzheimer’s Aβ(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat. Med. 3, 1021–1023.

    PubMed  CAS  Google Scholar 

  35. Hartmann T., Bieger S. C., Bruhl B., Tienari P. J., Ida N., Allsop D., et al. (1997) Distinct sites of intracellular production for Alzheimer’s disease Aβ40/42 amyloid peptides. Nat. Med. 3, 1016–1020.

    PubMed  CAS  Google Scholar 

  36. Skovronsky D. M., Doms R. W., and Lee V. M.-Y. (1998) Detection of a novel intraneuronal pool of insoluble amyloid β protein that accumulates with time in culture. J. Cell. Biol. 141, 1031–1039.

    PubMed  CAS  Google Scholar 

  37. Esch F. S., Keim P. S., Beattie E. C., Blacher R. W., Culwell A. R., Oltersdorf T., et al. (1990) Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248, 1122–1124.

    PubMed  CAS  Google Scholar 

  38. Skovronsky D. M., Moore D. B., Milla M. E., Doms R. W., and Lee V. M.-Y. (2000) Protein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-golgi network. J. Biol. Chem. 275, 2568–2575.

    PubMed  CAS  Google Scholar 

  39. Buxbaum J. D., Liu K. N., Luo Y., Slack J. L., Stocking K. L., Peschon J. J., et al. (1998) Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer’s amyloid protein precursor. J. Biol. Chem. 273, 27,765–27,767.

    CAS  Google Scholar 

  40. Lammich S., Kojro E., Postina R., Gilbert S., Pfeiffer R., Jasionowski M., et al. (1999) Constitutive adn regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloproteinase. Proc. Natl. Acad. Sci. USA 96, 3922–3927.

    PubMed  CAS  Google Scholar 

  41. Kang J., Lemaire H. G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K. H., et al. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736.

    PubMed  CAS  Google Scholar 

  42. Giaccone G., Tagliavini F., Linoli G., Bouras C., Frigerio L., Frangione B., and Bugiani O. (1989) Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques. Neurosci. Lett. 97, 232–238.

    PubMed  CAS  Google Scholar 

  43. Mann D. M., and Esiri M. M. (1989) The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J. Neurol. Sci. 89, 169–179.

    PubMed  CAS  Google Scholar 

  44. Motte J. and Williams R. S. (1989) Age-related changes in the density and morphology of plaques and neurofibrillary tangles in Down syndrome brain. Acta Neuropathol. 77, 535–546.

    PubMed  CAS  Google Scholar 

  45. Neve R. L., Finch E. A., and Dawes L. R. (1988) Expression of the Alzheimer amyloid precursor gene transcripts in the human brain. Neuron 1, 669–677.

    PubMed  CAS  Google Scholar 

  46. Tilley L., Morgan K., and Kalsheker N. (1998) Genetic risk factors in Alzheimer’s disease. Mol. Pathol. 51, 293–304.

    Article  PubMed  CAS  Google Scholar 

  47. Hardy J. (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci. 20, 154–159.

    PubMed  CAS  Google Scholar 

  48. Citron M., Oltersdorf T., Haass C., McConlogue L., Hung A. Y., Seubert P., et al. (1992) Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature 360, 672–674.

    PubMed  CAS  Google Scholar 

  49. Chartier-Harlin M. C., Crawford F., Houlden H, Warren A., Hughes D., Fidani L., et al. (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353, 844–846.

    PubMed  CAS  Google Scholar 

  50. Goate A., Chartier-Harlin M. C., Mullan M., Brown J., Crawford F., Fidani L., et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706.

    PubMed  CAS  Google Scholar 

  51. Murrell J., Farlow M., Ghetti B., and Benson M. D. (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 254, 97–99.

    PubMed  CAS  Google Scholar 

  52. Suzuki N., Cheung T. T., Cai X. D., Odaka A., Otvos L. Jr., Eckman C., et al. (1994) An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (β APP717) mutants. Science 264, 1336–1340.

    PubMed  CAS  Google Scholar 

  53. Hussain I, Powell D., Howlett D. R., Tew D. G., Meek T. D., Chapman C., et al. (1999) Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell Neurosci. 14, 419–427.

    PubMed  CAS  Google Scholar 

  54. Sinha S., Anderson J. P., Barbour R., Basi G. S., Caccavello R., Davis D., et al. (1999) Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540.

    PubMed  CAS  Google Scholar 

  55. Vassar R., Bennett B. D., Babu-Khan S., Kahn S., Mendiaz E. A., Denis P., et al. (1999) β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741.

    PubMed  CAS  Google Scholar 

  56. Yan R., Bienkowski M. J., Shuck M. E., Miao H., Tory M. C., Pauley A. M., et al. (1999) Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Nature 402, 533–537.

    PubMed  CAS  Google Scholar 

  57. Lin X., Koelsch G., Wu S., Downs D, Dashti A., and Tang J. (2000) Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc. Natl. Acad. Sci. USA 97, 1456–1460.

    PubMed  CAS  Google Scholar 

  58. Masters C. L., Simms G., Weinman N. A., Multhaup G., McDonald B. L., and Beyreuther K. (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. USA 82, 4245–4249.

    PubMed  CAS  Google Scholar 

  59. Masters C. L., Multhaup G., Simms G., Pottgiesser J., Martins R. N., and Beyreuther K. (1985) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as the amyloid plaque cores and blood vessels. EMBO J. 4, 2757–2763.

    PubMed  CAS  Google Scholar 

  60. Guiroy D. C., Miyazaki M., Multhaup G., Fisher P., Garruto R. M., Beyreuther K., et al. (1987) Amyloid of neurofibrillary tangles of Guamanian parkinsonism-dementia and Alzheimer disease share identical amino acid sequence. Proc. Natl. Acad. Sci. USA 84, 2073–2077.

    PubMed  CAS  Google Scholar 

  61. Gouras G. K., Xu H., Jovanovic J. N., Buxbaum J. D., Wang R., Greengard P., et al. (1998) Generation and regulation of β-amyloid peptide variants by neurons. J. Neurochem. 71, 1920–1925.

    Article  PubMed  CAS  Google Scholar 

  62. Citron M., Diehl T. S., Capell A., Haass C., Teplow D. B., and Selkoe D. J. (1996) Inhibition of amyloid β-protein production in neural cells by the serine protease inhibitor AEBSF. Neuron 17, 171–179.

    Google Scholar 

  63. Seubert P., Oltersdorf T., Lee M. G., Barbour R., Blomquist C., Davis D. L., et al. (1993) Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide. Nature 361, 260–263.

    PubMed  CAS  Google Scholar 

  64. Haass C., Hung A. Y., Schlossmacher M. G., Teplow D. B., and Selkoe D. J. (1993) β-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J. Biol. Chem. 268, 3021–3024.

    PubMed  CAS  Google Scholar 

  65. Knops J., Suomensaari S., Lee M., McConlogue L., Seubert P., and Sinha S. (1995) Cell-type and amyloid precursor protein-type specific inhibition of Aβ release by bafilomycin A1, a selective inhibitor of vacuolar ATPases. J. Biol. Chem. 270, 2419–2422.

    PubMed  CAS  Google Scholar 

  66. Citron M., Teplow D. B., and Selkoe D. J. (1995) Generation of amyloid β protein from its precursor is sequence specific. Neuron 14, 661–670.

    PubMed  CAS  Google Scholar 

  67. Capell A., Steiner H., Willem M., Kaiser H., Meyer C., Walter J., et al. (2000) Maturation and pro-peptide cleavage of β-secretase. J. Biol. Chem. 275, 30,849–30854.

    CAS  Google Scholar 

  68. Huse J. T., Pijak D. S., Leslie G. J., Lee V. M.-Y., and Doms R. W. (2000) Maturation and endosomal targeting of β-site amyloid precursor protein-cleaving enzyme: the Alzheimer’s disease β-secretase. J. Biol. Chem. 275, 33,729–33,737.

    CAS  Google Scholar 

  69. Haniu M., Denis P., Young Y., Mendiaz E. A., Fuller J., Hui J., et al. (2000) Characterization of Alzheimer’s β-secretase protein BACE. J. Biol. Chem. 275, 21,099–21,106.

    CAS  Google Scholar 

  70. Bennett B. D., Denis P., Haniu M., Teplow D. B., Kahn S., Louis J. C., et al. (2000) A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s β-secretase. J. Biol. Chem. 275, 37,712–37,717.

    CAS  Google Scholar 

  71. Hong L., Koelsch G., Lin X., Wu S., Terzyan S., Ghosh A., et al. (2000) Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science 290, 150–153.

    PubMed  CAS  Google Scholar 

  72. Sauder J. M., Arthur J. W., and Dunbrack R. L. (2000) Modeling of substrate specificity of the Alzheimer’s disease amyloid precursor protein β-secretase. J. Mol. Biol. 300, 241–248.

    PubMed  CAS  Google Scholar 

  73. Acquati F., Accarino M., Nucci C., Fumagalli P., Jovine L., Ottolenghi S., and Taramelli R. (2000) The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region. FEBS Lett. 468, 59–64.

    PubMed  CAS  Google Scholar 

  74. Bennett B. D., Babu-Khan S., Loeloff R., Louis J.-C., Curran E., Citron M., and Vassar R. (2000) Expression analysis of BACE2 in brain and peripheral tissues. J. Biol. Chem. 275, 20,647–20,651.

    CAS  Google Scholar 

  75. Solans A., Estivill X., and de La Luna S. (2000) A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer’s amyloid precursor protein β-secretase. Cytogenet. Cell Genet. 89, 177–184.

    PubMed  CAS  Google Scholar 

  76. Farzan M., Schnitzler C. E., Vasilieva N., Leung D., and Choe H. (2000) BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein. Proc. Natl. Acad. Sci. USA 97, 9712–9717.

    PubMed  CAS  Google Scholar 

  77. Levy-Lahad E., Wasco W., Poorkaj P., Romano D. M., Oshima J., Pettingell W. H. et al. (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977.

    PubMed  CAS  Google Scholar 

  78. Rogaev E. I., Sherrington R., Rogaeva E. A., Levesque G., Ikeda M., Liang Y., et al. (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778.

    PubMed  CAS  Google Scholar 

  79. Sherrington R., Rogaev E. I., Liang Y., Rogaeva E. A., Levesque G., Ikeda M., et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760.

    PubMed  CAS  Google Scholar 

  80. Doan A., Thinakaran G., Borchelt D. R., Slunt H. H., Ratovitsky T., Podlisny M., et al. (1996) Protein topology of presenilin 1. Neuron 17, 1023–1030.

    Google Scholar 

  81. Li X. and Greenwald I. (1996) Membrane topology of the C. elegans SEL-12 presenilin. Neuron 17, 1015–1021.

    Google Scholar 

  82. De Strooper B., Beullens M., Contreras B., Levesque L., Craessaerts K., Cordell B., et al. (1997) Phosphorylation, subcellular localization, and membrane orientation of the Alzheimer’ disease-associated presenilins. J. Biol. Chem. 272, 3590–3598.

    PubMed  Google Scholar 

  83. Dewji N. N. and Singer S. J. (1997) The seven-transmembrane spanning topography of the Alzheimer disease-related presenilin proteins in the plasma membranes of cultured cells. Proc. Natl. Acad. Sci. USA 94, 14,025–14,030.

    CAS  Google Scholar 

  84. Lehmann S., Chiesa R., and Harris D. A. (1997) Evidence for a six-transmembrane domain structure of presenilin 1. J. Biol. Chem. 272, 12,047–12,051.

    CAS  Google Scholar 

  85. Li X. and Greenwald I. (1998) Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc. Natl. Acad. Sci. USA 95, 7109–7114.

    PubMed  CAS  Google Scholar 

  86. Thinakaran G., Borchelt D. R., Lee M. K., Slunt H. H., Spitzer L., Kim G., et al. (1996) Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181–190.

    Google Scholar 

  87. Kim T.-W., Pettingell W. H., Hallmark O. G., Moir R. D., Wasco W., and Tanzi R. E. (1997) Endoproteolytic cleavage and proteosomal degradation of presenilin 2 in transfected cells. J. Biol. Chem. 272, 11,006–11,010.

    CAS  Google Scholar 

  88. Capell A., Grunberg J., Pesold B., Diehlmann A., Citron M., Nixon R., et al. (1998) The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100–150-kDa molecular mass complex. J. Biol. Chem. 273, 3205–3211.

    PubMed  CAS  Google Scholar 

  89. Yu G., Chen F., Levesque G., Nishimura M., Zhang D. M., Levesque L., et al. (1998) The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains β-catenin. J. Biol. Chem. 273, 16,470–16,475.

    CAS  Google Scholar 

  90. Thinakaran G., Harris C. L., Ratovitski T., Davenport F., Slunt H. H., Price D. L., et al. (1997) Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J. Biol. Chem. 272, 28,415–28,422.

    CAS  Google Scholar 

  91. Ratovitski T., Slunt H. H., Thinakaran G., Price D. L., Sisodia S. S., and Borchelt D. R. (1997) Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J. Biol. Chem. 272, 24,536–24,541.

    CAS  Google Scholar 

  92. Steiner H., Capell A., Pesold B., Citron M., Kloetzel P. M., Selkoe D. J., et al. (1998) Expression of Alzheimer’s disease-associated presenilin-1 is controlled by proteolytic degradation and complex formation. J. Biol. Chem. 273, 32,322–32,331.

    CAS  Google Scholar 

  93. Cook D. G., Sung J. C., Golde T. E., Felsenstein K. M., Wojczyk B. S., Tanzi R. E., et al. (1996) Expression and analysis of presenilin 1 in a human neuronal system: localization in cell bodies and dendrites. Proc. Natl. Acad. Sci. USA 93, 9223–9228.

    Google Scholar 

  94. Kovacs D. M., Fausett H. J., Page K. J., Kim T., Moir R. D., Merriam DE, et al. W. (1996) Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat. Med. 2, 224–229.

    Google Scholar 

  95. Annaert W., Levesque L., Craessaerts K., Dierinck I., Snellings G., Westaway D., et al. (1999) Presenilin 1 controls γ-secretase processing of amyloid precursor protein in pre-Golgi compartments of hippocampal neurons. J. Cell. Biol. 147, 277–294.

    PubMed  CAS  Google Scholar 

  96. Lah J. J. and Levey AI. (2000) Endogenous presenilin-1 targets to endocytic rather than biosynthetic compartments. Mol. Cell. Neurosci. 16, 111–126.

    PubMed  CAS  Google Scholar 

  97. Li J., Xu M., Zhou H., Ma J., and Potter H. (1997) Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell 90, 917–927.

    PubMed  CAS  Google Scholar 

  98. Schwarzman A. L., Singh N., Tsiper M., Gregori L., Dranovsky A., Vitek M. P., et al. (1999) Endogenous presenilin 1 redistributes to the surface of lamellipodia upon adhesion of Jurkat cells to a collagen matrix. Proc. Natl. Acad. Sci. USA 96, 7932–7937.

    PubMed  CAS  Google Scholar 

  99. Nowotny P., Gorski S. M., Han S. W., Philips K., Ray W. J., Nowotny V., et al. (2000) Posttranslational modification and plasma membrane localization of the Drosophila melanogaster presenilin. Mol. Cell. Neurosci. 15, 88–98.

    PubMed  CAS  Google Scholar 

  100. Ray W. J., Yao M., Mumm J., Schroeter E. H., Saftig P., Wolfe M., et al. (1999) Cell surface presenilin-1 participates in the γ-secretase-like proteolysis of notch. J. Biol. Chem. 274, 36,801–36,807.

    CAS  Google Scholar 

  101. Levitan D. and Greenwald I. (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377, 351–354.

    PubMed  CAS  Google Scholar 

  102. Shen J., Bronson R. T., Chen D. F., Xia W., Selkoe D. J., and Tonegawa S. (1997) Skeletal and CNS defects in presenilin-1-deficient mice. Cell 89, 629–639.

    PubMed  CAS  Google Scholar 

  103. Wong P. C., Zheng H., Chen H., Becher M. W., Sirinathsingh D. J. S., Trumbauer M. E., et al. (1997) Presenilin is required for Notch1 and Dll1 expression in the paraxial mesoderm. Nature 387, 288–292.

    PubMed  CAS  Google Scholar 

  104. Swiatek P. J., Lindsell C. E., Franco del Amo F., Weinmaster G., and Gridley T. (1994) Notch1 is essential for postimplantation development in mice. Genes Dev. 8, 707–719.

    PubMed  CAS  Google Scholar 

  105. Conlon R. A., Reaume A. G., and Rossant J. (1995) Notch1 is required for the coordinate segmentation of somites. Development 121, 1533–1545.

    PubMed  CAS  Google Scholar 

  106. Donoviel D. B., Hadjantonakis A., Ikeda M., Zheng H., St. George-Hyslop P., and Bernstein A. (1999) Mice lacking both presenilin genes exhibit early embryonic patterning defects. Genes Dev. 13, 2801–2810.

    PubMed  CAS  Google Scholar 

  107. Herreman A., Hartmann D., Annaert W., Saftig P., Craessaerts K., Serneels L., et al. (1999) Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency. Proc. Natl. Acad. Sci. USA 96, 11,872–11,877.

    CAS  Google Scholar 

  108. Vito P., Lacana E., and D’Adamio L. (1996) Interfering with apoptosis: Ca2+-binding protein A1G-2 and Alzheimer’s disease gene ALG-3. Science 271, 521–525.

    Google Scholar 

  109. Vito P., Ghayur T., and D’Adamio L. (1997) Generation of anti-apoptotic presenilin-2 polypeptides by alternative transcription, proteolysis, and caspase-3 cleavage. J. Biol. Chem. 272, 28,315–28,320.

    CAS  Google Scholar 

  110. Deng G., Pike C. J., and Cotman C. W. (1996) Alzheimer-associated presenilin-2 confers increased sensitivity to apoptosis in PC12 cells. FEBS Lett. 397, 50–54.

    Google Scholar 

  111. Guo Q., Furukawa K., Sopher B. L., Pham D. G., Xie J., Robinson N., et al. (1996) Alzheimer’s PS-1 mutation perturbs calcium homoeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide. Neuroreport 8, 379–383.

    Article  Google Scholar 

  112. Wolozin B, Iwasaki K., Vito P., Ganjei J. K., Lacana E., Sunderland T., et al. (1996) Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science 274, 1710–1713.

    Google Scholar 

  113. Janicki S. and Monteiro M. J. (1997) Increased apoptosis arising from increased expression of the Alzheimer’s disease-associated presenilin-2 mutation (N1411). J. Cell. Biol. 139, 485–495.

    PubMed  CAS  Google Scholar 

  114. De Strooper B., Saftig P., Craessaerts K., Vanderstichele H., Guhde G., Annaert W., et al. (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387–390.

    PubMed  Google Scholar 

  115. Naruse S., Thinakaran G., Luo J., Kusiak J. W., Tomita T., Iwatsubo T., et al. (1998) Effects of PS1 deficiency on membrane protein trafficking in neurons. Neuron 21, 1213–1221.

    PubMed  CAS  Google Scholar 

  116. Zhou J., Lyanage U., Medina M., Ho C., Simmons A. D., Lovett M., and Kosik K. S. (1997) Presenilin 1 interaction in the brain with a novel member of the Armadillo family. Neuroreport 8, 1489–1494.

    Article  PubMed  CAS  Google Scholar 

  117. Buxbaum J. D., Choi E.-K., Luo Y., Lilliehook C., Crowley A. C., Merriam D. E., and Wasco W. (1998) Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Nat. Med. 4, 1177–1181.

    PubMed  CAS  Google Scholar 

  118. Smine A., Xu X., Nishiyama K., Katada T., Gambett P., Yadav S. P., et al. (1998) Regulation of brain G-protein G0 by Alzheimer’s disease gen presenilin-1. J. Biol. Chem. 273, 16,281–16,288.

    CAS  Google Scholar 

  119. Takashima A., Murayama M., Murayama O., Kohno T., Honda T., Yasutake K., et al. (1998) Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau. Proc. Natl. Acad. Sci. USA 95, 9637–9641.

    PubMed  CAS  Google Scholar 

  120. Zhang W., Han S. W., McKeel D. W., Goate A., and Wu J. Y. (1998) Interaction of presenilins with the filamin family of actin-binding proteins. J. Neurosci. 18, 914–922.

    PubMed  CAS  Google Scholar 

  121. Georgakopoulos A., Marambaud P., Efthimiopoulos S., Shioi J., Cui W., Li H. C., et al. (1999) Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Mol. Cell 4, 893–902.

    PubMed  CAS  Google Scholar 

  122. Imafuku I., Masaki T., Waragai M., Takeuchi S., Kawabata M., Hirai S.-I., et al. (1999) Presenilin 1 suppresses the function of c-Jun homodimers via interaction with QM/Jif-1. J. Cell. Biol. 147, 121–133.

    PubMed  CAS  Google Scholar 

  123. Stabler S. M., Ostrowski L. L., Janicki S. M., and Monteiro M. J. (1999) A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer’s disease presenilin 2 protein. J. Cell. Biol. 145, 1277–1292.

    PubMed  CAS  Google Scholar 

  124. Borchelt D. R., Thinakaran G., Eckman C. B., Lee M. K., Davenport F., Ratovitsky T., et al. (1996) Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005–1013.

    Google Scholar 

  125. Duff K., Eckman C., Zehr C., Yu X., Prada C.-M., Perez-tur J., et al. (1996) Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713.

    Google Scholar 

  126. Lemere C. A., Lopera F., Kosik K. S., Lendon C. L., Ossa J., Saido T., et al. (1996) The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology. Nat. Med. 2, 1146–1150.

    Google Scholar 

  127. Scheuner D., Eckman C., Jensen M., Song X., Citron M., Suzuki N., et al. (1996) Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease in increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat. Med. 2, 864–870.

    Google Scholar 

  128. Borchelt D. R., Ratovitski T., van Lare J., Lee M. K., Gonzales V., Jenkins N. A., et al. (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939–945.

    PubMed  CAS  Google Scholar 

  129. Citron M., Westaway D., Xia W., Carlson G., Diehl T., Levesque G., et al. (1997) Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat. Med. 3, 67–72.

    PubMed  CAS  Google Scholar 

  130. Tomita T., Murayama K., Saido T. C., Kume H., Shinozaki K., Tokuhiro S., et al. (1997) The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid β protein ending at the 42nd (or 43rd) residue. Proc. Natl. Acad. Sci. USA 94, 2025–2030.

    PubMed  CAS  Google Scholar 

  131. Xia W., Zhang J., Kholodenko D., Citron M., Podlisny M. B., Teplow D. B., et al. (1997) Enhanced production and oligomerization of the 42-residue amyloid β-protein by Chinese hamster ovary cells stably expressing mutant presenilins. J. Biol. Chem. 272, 7977–7982.

    PubMed  CAS  Google Scholar 

  132. Sudoh S., Kawamura Y., Sato S., Wang R., Saido T. C., Oyama F., et al. (1998) Presenilin 1 mutations linked to familial Alzheimer’s disease increase the intracellular levels of amyloid β-protein 1–42 and its N-terminally truncated variant(s) which are generated at distinct sites. J. Neurochem. 71, 1535–1543.

    Article  PubMed  CAS  Google Scholar 

  133. Nakano Y., Kondoh G., Kudo T., Imaizumi K., Kato M., Miyazaki J.-I., et al. (1999) Accumulation of murine amyloidβ42 in a gene-dosage-dependent manner in PS1 ‘knock-in’ mice. Eur. J. Neurosci. 11, 2577–2581.

    PubMed  CAS  Google Scholar 

  134. Davis J. A., Naruse S., Chen H., Eckman C., Younkin S., Price D. L., et al. (1998) An Alzheimer’s disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos. Neuron 20, 603–609.

    PubMed  CAS  Google Scholar 

  135. Qian S., Jiang P., Guan X.-M., Singh G., Trumbauer M. E., Yu H., et al. (1998) Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1-42/43 expression. Neuron 20, 611–617.

    PubMed  CAS  Google Scholar 

  136. Herreman A., Serneels L., Annaert W., Collen D., Schoonjans L., and De Strooper B. (2000) Total inactivation of γ-secretase activity in presenilin-deficient embryonic stem cells. Nat. Cell Biol. 2, 461–462.

    PubMed  CAS  Google Scholar 

  137. Zhang Z., Nadeau P., Song W., Donoviel D., Yuan M., Bernstein A., and Yankner B. A. (2000) Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch. Nat. Cell Biol. 2, 463–465.

    PubMed  CAS  Google Scholar 

  138. Wolfe M. S., Xia W., Ostaszewski B. L., Diehl T. S., Kimberly W. T., and Selkoe D. J. (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517.

    PubMed  CAS  Google Scholar 

  139. Kimberly W. T., Xia W., Rahmati T., Wolfe M. S., and Selkoe D. J. (2000) The transmembrane aspartates in presenilin 1 and 2 are obligatory for γ-secretase activity and amyloid β-protein generation. J. Biol. Chem. 275, 3173–3178.

    PubMed  CAS  Google Scholar 

  140. Li Y.-M., Lai M.-T., Xu M., Huang Q., DiMuzio-Mower J., Sardana M. K., et al. (2000) Presenilin 1 is linked with γ-secretase activity in the detergent solubilized state. Proc. Natl. Acad. Sci. USA 97, 6138–6143.

    PubMed  CAS  Google Scholar 

  141. Xia W., Ray W. J., Ostaszewski B. L., Rahmati T., Kimberley W. T., Wolfe M. S., et al. (2000) Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid β-protein generation. Proc. Natl. Acad. Sci. USA 97, 9299–9304.

    PubMed  CAS  Google Scholar 

  142. Esler W. P., Kimberly W. T., Ostaszewski B. L., Diehl T. S., Moore C. L., Tsai J. Y., et al. (2000) Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat. Cell Biol. 2, 428–434.

    PubMed  CAS  Google Scholar 

  143. Li Y. M., Xu M., Lai M. T., Huang Q., Castro J. L., DiMuzio-Mower J., et al. (2000) Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689–694.

    PubMed  CAS  Google Scholar 

  144. Kopan R., Schroeter E. H., Weintraub H., and Nye J. S. (1996) Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. Proc. Natl. Acad. Sci. USA 93, 1683–1688.

    Google Scholar 

  145. Schroeter E. H., Kisslinger J. A., and Kopan R. (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382–386.

    PubMed  CAS  Google Scholar 

  146. Struhl G. and Adachi A. (1998) Nuclear access and action for notch in vivo. Cell 93, 649–660.

    PubMed  CAS  Google Scholar 

  147. De Strooper B., Annaert W., Cupers P., Saftig P., Craessaerts K., Mumm J. S., et al. (1999) A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522.

    PubMed  Google Scholar 

  148. Song W., Nadeau P., Yuan M., Yang X., Shen J., and Yankner B. A. (1999) Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc. Natl. Acad. Sci. USA 96, 6959–6963.

    PubMed  CAS  Google Scholar 

  149. Struhl G. and Greenwald I. (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398, 522–525.

    PubMed  CAS  Google Scholar 

  150. Kulic L., Walter J., Multhaup G., Teplau D. B., Baumeister R., Romig H., Capell A., et al. (2000) Separation of presenilin function in amyloid β-peptide generation and endoproteolysis of Notch. Proc. Natl. Acad. Sci. USA 97, 5913–5918.

    PubMed  CAS  Google Scholar 

  151. Mori K. (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101, 451–454.

    PubMed  CAS  Google Scholar 

  152. Niwa M., Sidrauski C., Kaufman R. J., and Walter P. (1999) A role for presenilin-1 in nuclear accumulation of Ire1 fragments and induction of the mammalian unfolded protein response. Cell 99, 691–702.

    PubMed  CAS  Google Scholar 

  153. Katayama T., Imaizumi K., Sato N., Miyoshi K., Kudo T., Hitomi J., et al. (1999) Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat. Cell Biol. 1, 479–485.

    PubMed  CAS  Google Scholar 

  154. Murphy M. P., Uljon S. N., Fraser P. E., Fauq A., Lookingbill H. A., Findlay K. A., et al. (2000) Presenilin 1 regulates pharmacologically distinct γ-secretase activities. Implications for the role of presenilin in γ-secretase cleavage. J. Biol. Chem. 275, 26,277–26,284.

    CAS  Google Scholar 

  155. Yu G., Chen F., Nishimura M., Steiner H., Tandon A., Kawarai T., et al. (2000) Mutation of conserved aspartates affects maturation of both aspartate mutant and endogenous presenilin 1 and presenilin 2 complexes. J. Biol. Chem. 275, 27,348–27,353.

    CAS  Google Scholar 

  156. Yu G., Nishimura M., Arawaka S., Levitan D., Zhang L., Tandon A., et al. (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407, 48–54.

    PubMed  CAS  Google Scholar 

  157. Schenk D., Barbour R., Dunn W., Gordon G., Grajeda H., Guido T., et al. (1999) Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177.

    PubMed  CAS  Google Scholar 

  158. Bard F., Cannon C., Barbour R., Burke R. L., Games D., Grajeda H., et al. (2000) Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of alzheimer disease. Nat. Med. 6, 916–919.

    PubMed  CAS  Google Scholar 

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    Jason T. Huse & Robert W. Doms

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Huse, J.T., Doms, R.W. Closing in on the amyloid cascade. Mol Neurobiol 22, 81–98 (2000). https://doi.org/10.1385/MN:22:1-3:081

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