Journal of Molecular Neuroscience

, Volume 17, Issue 2, pp 157–170

The β-secretase, BACE

A prime drug target for Alzheimer’s disease
Article

Abstract

Evidence suggests that the β-amyloid peptide (Aβ) is central to the pathophysiology of Alzheimer’s disease (AD). Amyloid plaques, primarily composed of Aβ, progressively develop in the brains of AD patients, and mutations in three genes (APP, PS1, and PS2) cause early onset familial AD (FAD) by directly increasing synthesis of the toxic, plaque-promoting Aβ42 peptide. Given the strong association between Aβ and AD, therapeutic strategies to lower the concentration of Aβ in the brain should prove beneficial for the treatment of AD. One such strategy would involve inhibiting the enzymes that generate Aβ. Aβ is a product of catabolism of the large TypeI membrane protein, amyloid precursor protein (APP). Two proteases, called β- and γ-secretase, mediate the endoproteolysis of APP to liberate the Aβ peptide. For over a decade, the molecular identities of these proteases were unknown. Recently, the γ-secretase has been tentatively identified as the presenilin proteins, PS1 and PS2, and the identity of the β-secretase has been shown to be the novel transmembrane aspartic protease, β-site APP cleaving enzyme 1 (BACE1; also called Asp2 and memapsin2). BACE2, a novel protease homologous to BACE1, was also identified, and together the two enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the properties of the β-secretase, and as the key rate-limiting enzyme that initiates the formation of Aβ, BACE1 is an attractive drug target for AD. Here, I review the identification and initial characterization of BACE1 and BACE2, and summarize our current understanding of BACE1 post-translational processing and intracellular trafficking. In addition, I discuss recent studies of BACE1 knockout mice and the BACE1 X-ray structure, and relate implications for BACE1 drug development.

Index Entries

β-Secretase BACE Alzheimer’s disease Aβ peptide β-amyloid APP processing 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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.PubMedCrossRefGoogle Scholar
  2. Benjannet S., Elagoz A., Wickham L., Mamarbachi M., Munzer J. S., Basak A., et al. (2001) Post-translational processing of β-secretase (β-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-β production. J. Biol. Chem. 276, 10,879–10,887.CrossRefGoogle Scholar
  3. Bennett B. D., Babu-Khan S., Loeloff R., Louis J.-C., Curran E., Citron M., and Vassar R. (2000a) Expression analysis of BACE2 in brain and peripheral tissues. J. Biol. Chem. 275, 20,647–20,651.Google Scholar
  4. Bennett B. D., Denis P., Haniu M., Teplow D. B., Kahn S., Louis J.-C., Citron M., and Vassar R. (2000b) A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s β-secretase. J. Biol. Chem. 275, 37,712–37,717.Google Scholar
  5. Bodendorf U., Fischer F., Bodian D., Multhaup G., and Paganetti P. (2001) A splice variant of β-secretase deficient in the amyloidogenic processing of the amyloid precursor protein. J. Biol. Chem. 276, 12,019–12,023.CrossRefGoogle Scholar
  6. Buxbaum J. D., Liu K. N., Luo Y., Slack J. L., Stocking K. L., Peschon J. J., Johnson R. S., Castner B. J., Cerretti D. P., and Black R. A. (1998) 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, 27,765–27,767.CrossRefGoogle Scholar
  7. Cai H., Wang Y., McCarthy D., Wen H., Borchelt D. R., Price D. L., and Wong P. C. (2001) BACE1 is the major β-secretase for generation of Aβ peptides by neurons. Nature Neurosci. 4, 233–234.PubMedCrossRefGoogle Scholar
  8. Capell A., Steiner H., Willem M., Kaiser H., Meyer C., Walter J., Lammich S., Multhaup G., and Haass C. (2000) Maturation and pro-peptide cleavage of β-secretase. J. Biol. Chem. 275, 30,849–30,854.CrossRefGoogle Scholar
  9. Charlwood J., Dingwall C., Matico R., Hussain I., Johanson K., Moore S., et al. (2001) Characterization of the glycosylation profiles of Alzheimer’s β-secretase protein Asp-2 expressed in a variety of cell lines. J. Biol. Chem. 276, 16,739–16,748.CrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. Creemers J. W., Ines Dominguez D., Plets E., Serneels L., Taylor N. A., Multhaup G., Craessaerts K., Annaert W., and De Strooper B. (2001) Processing of β-secretase by furin and other members of the proprotein convertase family. J. Biol. Chem. 276, 4211–4217.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. Gandy S. and Greengard P. (1992) Amyloidogenesis in Alzheimer’s disease: Some possible therapeuticopportunities. Trends Pharm. Sci. 13, 108–113.PubMedCrossRefGoogle Scholar
  15. Ghosh A. K., Shin D., Downs D., Koelsch G., Lin X., Ermolieff J., and Tang J. (2000) Design of potent inhibitors for human brain memapsin 2 (β-secretase). J. Am. Chem. Soc. 122, 3522–3523.CrossRefGoogle Scholar
  16. 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. Commun. 120, 885–890.PubMedCrossRefGoogle Scholar
  17. Gouras G. K., Xu H., Jovanovic J. N., Buxbaum J. D., Wang R., Greengard P., Relkin N. R., and S. G. (1998) Generation and regulation of β-amyloid peptide variants by neurons. J. Neurochem. 71, 1920–1925.PubMedCrossRefGoogle Scholar
  18. Haass C., Capell A., Citron M., Teplow D. B., and Selkoe D. J. (1995) The vacuolar H+ ATPase inhibitor bafilomycin A1 differentially affects proteolytic processing of mutant and wild-type β-amyloid precursor protein. J. Biol. Chem. 270, 6186–6192.PubMedCrossRefGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. Haass C., Lemere C. A., Capell A., Citron M., Seubert P., Schenk D., Lannfelt L., and Selkoe D. J. (1995) The Swedish mutation causes early-onset Alzheimer’s disease by β-secretase cleavage within the secretory pathway. Nature Med. 1, 1291–1296.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. Haniu M., Denis P., Young Y., Mendiaz E. A., Fuller J., Hui J. O., et al. (2000). Characterization of Alzheimer’s β-secretase protein BACE. J. Biol. Chem. 275, 21,099–21,106.CrossRefGoogle Scholar
  23. Hong L., Koelsch G., Lin X., Wu S., Terzyan S., Ghosh A. K., Zhang X. C., and Tang J. (2000) Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science 290, 150–153.PubMedCrossRefGoogle Scholar
  24. Hsiao K., Chapman P., Nilsen S., Eckman C., Harigaya Y., Younkin S., Yang F., and Cole G. (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–103.PubMedCrossRefGoogle Scholar
  25. Huse J. T., Pijak D. S., Leslie G. J., Lee V. M., 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.CrossRefGoogle Scholar
  26. Hussain I., Christie G., Schneider K., Moore S., and Dingwall C. (2001) Prodomain processing of Asp1 (BACE2) is autocatalytic. J. Biol. Chem. 276, 23,322–23,328.CrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. Hussain I., Powell D. J., Howlett D. R., Chapman G. A., Gilmour L., Murdock P. R., et al. (2000) ASP1 (BACE2) cleaves the amyloid precursor protein at the β-secretase site. Mol. Cell. Neurosci. 16, 609–619.PubMedCrossRefGoogle Scholar
  29. Hutton M., Perez-Tur J., and Hardy J. (1998) Genetics of Alzheimer’s disease. Essays Biochem. 33, 117–131.PubMedGoogle Scholar
  30. Kang J., Lemaire H.-G., Unterbeck A., Salbum J. M., Masters C. L., Grzeschik K.-H., Multhaup G., Beyreuther K., and Muller-Hill B. (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733–736.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. Koo E. H. and Squazzo S. (1994) Evidence that production and release of amyloid β-protein involves the endocytic pathway. J. Biol. Chem. 269, 17,386–17,389.Google Scholar
  33. Lammich S., Kojro E., Postina R., Gilbert S., Pfeiffer R., Jasionowski M., Haass C., and Fahrenholz F. (1999) Constitutive and Regulated Alpha-Secretase Cleavage of Alzheimer’s Amyloid Precursor Protein by a Disintegrin Metalloprotease. Proc. Natl. Acad. Sci. USA 96, 3922–3927.PubMedCrossRefGoogle Scholar
  34. Lee V. M.-Y., Balin B. J., Otvos L., and Trojanowski J. Q. (1991) A68. A major subunit of paired helical filaments and derivatized forms of normal tau. Science 251, 675–678.PubMedCrossRefGoogle Scholar
  35. Lin X., Koelsch G., Wu S., Downs D., Dashti A., and Tang J. (2000) Human aspartic protease memapsin 2 cleaves the β-secretase sites of β-amyloid precursor protein. Proc. Natl. Acad. Sci. USA 97, 1456–1460.PubMedCrossRefGoogle Scholar
  36. Lopez-Perez E., Zhang Y., Frank S. J., Creemers J., Seidah N., and Checler F. (2001) Constitutive α-secretase cleavage of the β-amyloid precursor protein in the furindeficient LoVo cell line: involvement of the pro-hormone convertase 7 and the disintegrin metalloprotease ADAM10. J. Neurochem. 76, 1532–1539.PubMedCrossRefGoogle Scholar
  37. Luo Y., Bolon B., Kahn S., Bennett B. D., Babu-Khan S., Denis P., et al. (2001) Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nature Neurosci. 4, 231–232.PubMedCrossRefGoogle Scholar
  38. Marcinkeviciene J., Luo Y., Graciani N. R., Combs A. P., and Copeland R. A. (2001) Mechanism of inhibition of β-site amyloid precursor protein-cleaving enzyme (BACE) by a statine-based peptide. J. Biol. Chem. 276, 23,790–23,794.CrossRefGoogle Scholar
  39. Marcinkiewicz M. and Seidah N. G. (2000) Coordinated expression of β-amyloid precursor protein and the putative β-secretase BACE and α-secretase ADAM10 in mouse and human brain. J. Neurochem. 75, 2133–2143.PubMedCrossRefGoogle Scholar
  40. Mullan M., Crawford F., Houlden H., Axelman K., Lilius L., Winblad B., and Lannfelt L. (1992a) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Nat. Genet. 1, 345–347.PubMedCrossRefGoogle Scholar
  41. Murphy T., Yip A., Brayne C., Easton D., Evans J. G., Xuereb J., Cairns N., Esiri M. M., and Rubinsztein D. C. (2001) The BACE gene: genomic structure and candidate gene study in late-onset Alzheimer’s disease. Neuroreport 12, 631–634.PubMedCrossRefGoogle Scholar
  42. 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.Google Scholar
  43. Roberds S. L., Anderson J., Basi G., Bienkowski M. J., Branstetter D. G., Chen K. S., et al. (2001) BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum. Mol. Genet. 10, 1317–1324.PubMedCrossRefGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. Sauder J. M., Arthur J. W., and Dunbrack R. L. Jr. (2000) Modeling of substrate specificity of the Alzheimer’s disease amyloid precursor protein β-secretase. J. Mol. Biol. 300, 241–248.PubMedCrossRefGoogle Scholar
  46. Saunders A. J., Kim T.-W., Tanzi R. E., Fan W., Bennett B. D., Babu-Khan S., et al. (1999) BACE maps to chromosome 11 and a BACE homolog, BACE2, reside in the obligate Down syndrome region of chromosome 21. Science 286, 1255a.Google Scholar
  47. Selkoe D. J. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766.PubMedGoogle Scholar
  48. Seubert P., Oltersdorf T., Lee M. G., Barbour R., Blomqist 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.PubMedCrossRefGoogle Scholar
  49. Shi X.-P., Chen E., Yin K.-C., Na S., Garsky V. M., Lai M.-T., et al. (2001) The pro domain of β-secretase does not confer strict zymogen-like properties but does assist proper folding of the protease domain. J. Biol. Chem. 276, 10,366–10,373.Google Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. Sisodia S. S., Kim S. H., and Thinakaran G. (1999) Function and dysfunction of the presenilins. Am. J. Hum. Genet. 65, 7–12.PubMedCrossRefGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A. B., St. George-Hyslop P. H., Van Keuren M. L., et al. (1987) Amyloid β-protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235, 880–884.PubMedCrossRefGoogle Scholar
  54. Terry R. D., Masliah E., and Hansen L. A. (1999) The neuropathology of Alzheimer disease and the structural basis of its cognitive alterations, in Alzheimer Disease (Terry R. D., Katzman R., Bick K. L., and Sisodia S. S., eds.) Lippincott Williams and Wilkins, Philadelphia, pp. 187–206.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.PubMedCrossRefGoogle Scholar
  56. Vassar R. and Citron M. (2000) Aβ-generating enzymes: recent advances in β- and γ-secretase research. Neuron 27, 419–422.PubMedCrossRefGoogle Scholar
  57. Walter J., Fluhrer R., Hartung B., Willem M., Kaether C., Capell A., Lammich S., Multhaup G., and C. H. (2001) Phosphorylation regulates intracellular trafficking of β-secretase. J. Biol. Chem. 276, 14,634–14,641.Google Scholar
  58. Wolfe M. S., Angeles J. D. L., Miller D. D., Xia W., and Selkoe D. J. (1999) Are Presenilins Intramembrane-Cleaving Proteases? Implications for the Molecular Mechanism of Alzheimer’s Disease. Biochemistry 38, 11,223–11,230.Google Scholar
  59. 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 Gamma-Secretase Activity. Nature 398, 513–517.PubMedCrossRefGoogle Scholar
  60. Yan R., Bienkowski M. J., Shuck M. E., Miao H., Tory M. C., Pauley A. M., Brashler J. R., Stratman N. C., Mathews W. R., Buhl A. E., Carter D. B., Tomasselli A. G., Parodi L. A., Heinrikson R. L., and Gurney M. E. (1999) Membrane-anchored Aspartyl Protease with Alzheimer’s Disease β-Secretase Activity. Nature 402, 533–537.PubMedCrossRefGoogle Scholar
  61. Yan R., Munzner J. B., Shuck M. E., and Bienkowski M. J. BACE2 functions as an alternative α-secretase in cells. J. Biol. Chem. (2001) 276, 34,019–34,027.Google Scholar
  62. Younkin S. G. (1998) The Role of A Beta 42 in Alzheimer’s Disease. J. Physiol. (Paris) 92, 289–292.CrossRefGoogle Scholar
  63. Zhao J., Paganini L., Mucke L., Gordon M., Refolo L., Carman M., Sinha S., Oltersdorf T., Lieberburg I., and McConlogue L. (1996). β-Secretase processing of the β-amyloid precursor protein in transgenic mice is efficient in neurons but inefficient in astrocytes. J. Biol. Chem. 271, 31,407–31,411.Google Scholar

Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  1. 1.Department of Cell and Molecular BiologyNorthwestern University Medical SchoolChicago

Personalised recommendations