Journal of Molecular Neuroscience

, Volume 23, Issue 1–2, pp 105–113 | Cite as

Bace 1

The β-secretase enzyme in alzheimer’s disease
Review Article

Abstract

Data that have accumulated for well over a decade have implicated the β-amyloid (Aβ) peptide as a central player in the pathogenesis of Alzheimer’s disease (AD). Amyloid plaques, composed primarily of Aβ progressively form in the brains of AD patients, and mutations in three genes (amyloid precursor protein [APP] and presenilin 1 and 2 [PS1 and PS2]) cause early-onset familial AD (FAD) by directly increasing production of the toxic, plaque-promoting Aβ42 peptide. Given the strong association between Aβ and AD, it is likely that therapeutic strategies to lower the levels of Aβ in the brain should prove beneficial for the treatment of AD. One such strategy could involve inhibiting the enzymes that generate Aβ. Aβ is a product of catabolism of the large type-I membrane protein APP. Two proteases, called β- and γ-secretase, endoproteolyze APP to liberate the Aβ peptide. Recently, the molecules responsible for these proteolytic activities have been identified. Several lines of evidence suggest that the PS1 and PS2 proteins are γ-secretase, and the identity of β-secretase has been shown to be the novel transmembrane aspartic protease, β-site APP-cleaving enzyme 1 (BACE1; also called Asp2 and memapsin 2). BACE2, a protease homologous to BACE1, was also identified, and together the two enzymes define a new family of transmembrane aspartic proteases. BACE1 exhibits all the functional properties of β-secretase, and as the key enzyme that initiates the formation of Aβ, BACE1 is an attractive drug target for AD. This review discusses the identification and initial characterization of BACE1 and BACE2, and summarizes recent studies of BACE1 knockout mice that have validated BACE1 as the authentic β-secretase in vivo.

Index Entries

Alzheimer’s disease β-amyloid Aβ peptide amyloid precursor protein β-secretase BACE1 BACE2 β-site APP clearing enzyme 

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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. 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, 20647–20651.PubMedCrossRefGoogle Scholar
  3. Bennett B. D., Denis P., Haniu M., Teplow D. B., Kahn S., Louis J.-C., et al. (2000b) A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s β-secretase. J. Biol. Chem. 275, 37712–37717.PubMedCrossRefGoogle Scholar
  4. 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, 12019–12023.PubMedCrossRefGoogle Scholar
  5. 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 alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 27765–27767.PubMedCrossRefGoogle Scholar
  6. 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. Nat. Neurosci. 4, 233–234.PubMedCrossRefGoogle Scholar
  7. 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
  8. 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
  9. 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
  10. Gandy S. and Greengard P. (1992) Amyloidogenesis in Alzheimer’s disease: Some possible therapeutic opportunities. Trends Pharmacol. Sci. 13, 108–113.PubMedCrossRefGoogle Scholar
  11. 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
  12. 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.PubMedCrossRefGoogle Scholar
  13. Haass C., Capell A., Citron M., Teplow D. B., and Selkoe D. J. (1995a) 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
  14. 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
  15. Haass C., Lemere C. A., Capell A., Citron M., Seubert P., Schenk D., et al. (1995b) The Swedish mutation causes early-onset Alzheimer’s disease by β-secretase cleavage within the secretory pathway. Nat. Med. 1, 1291–1296.PubMedCrossRefGoogle Scholar
  16. 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
  17. 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, 21099–21106.PubMedCrossRefGoogle Scholar
  18. Hsiao K., Chapman P., Nilsen S., Eckman C., Harigaya Y., Younkin S., et al. (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–103.PubMedCrossRefGoogle Scholar
  19. 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
  20. 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
  21. Hutton M., Perez-Tur J., and Hardy J. (1998) Genetics of Alzheimer’s disease. Essays Biochem. 33, 117–131.PubMedGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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
  24. Koo E. H. and Squazzo S. (1994) Evidence that production and release of amyloid β-protein involves the endocytic pathway. J. Biol. Chem. 269, 17386–17389.PubMedGoogle Scholar
  25. Lammich S., Kojro E., Postina R., Gilbert S., Pfeiffer R., Jasionowski M., et al. (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
  26. 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
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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. Nat. Neurosci. 4, 231–232.PubMedCrossRefGoogle Scholar
  29. 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
  30. 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
  31. Murphy T., Yip A., Brayne C., Easton D., Evans J. G., Xuereb J., et al. (2001) The BACE gene: genomic structure and candidate gene study in late-onset Alzheimer’s disease. Neuroreport 12, 631–634.PubMedCrossRefGoogle Scholar
  32. Pike C. J., Overman M. J., and Cotman C. W. (1995) Aminoterminal deletions enhance aggregation of β-amyloid peptides in vitro. J. Biol. Chem. 270, 23895–23898.PubMedCrossRefGoogle Scholar
  33. 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
  34. 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
  35. 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
  36. Selkoe D. J. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766.PubMedGoogle Scholar
  37. 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
  38. 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
  39. 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
  40. 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
  41. 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
  42. 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, PA, pp. 187–206.Google Scholar
  43. 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
  44. Vassar R. and Citron M. (2000) Aβ-generating enzymes: recent advances in β- and γ-secretase research. Neuron 27, 419–422.PubMedCrossRefGoogle Scholar
  45. Wolfe M. S., Angeles J. D. L., Miller D. D., Xia W., and Selkoe D. J. (1999a) Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer’s disease. Biochemistry 38, 11223–11230.PubMedCrossRefGoogle Scholar
  46. Wolfe M. S., Xia W., Ostaszewski B. L., Diehl T. S., Kimberly W. T., and Selkoe D. J. (1999b) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398, 513–517.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. Yan R., Munzner J. B., Shuck M. E., and Bienkowski M. J. (2001) BACE2 functions as an alternative αsecretase in cells. J. Biol. Chem. 276, 34019–34027.PubMedCrossRefGoogle Scholar
  49. Younkin S. G. (1998) The role of a beta 42 in Alzheimer’s disease. J. Physiol. (Paris) 92, 289–292.CrossRefGoogle Scholar
  50. Zhao J., Paganini L., Mucke L., Gordon M., Refolo L., Carman M., et al. (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, 31407–31411.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  1. 1.Department of Cell and Molecular BiologyThe Feinberg School of Medicine, Northwestern UniversityChicago

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