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  Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation

Fluhrer, R., Multhaup, G., Schlicksupp, A., Okochi, M., Takeda, M., Lammich, S., et al. (2003). Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation. Journal of Biological Chemistry, 278(8), 5531-5538.

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Genre: Zeitschriftenartikel
Alternativer Titel : J. Biol. Chem.

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 Urheber:
Fluhrer, R., Autor
Multhaup, G., Autor
Schlicksupp, A., Autor
Okochi, M., Autor
Takeda, M., Autor
Lammich, S., Autor
Willem, M.1, Autor           
Westmeyer, G., Autor
Bode, W.2, 3, 4, Autor           
Walter, J., Autor
Haass, C., Autor
Affiliations:
1External Organizations, ou_persistent22              
2Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              
3Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              
4Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565144              

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 Zusammenfassung: The beta-amyloid precursor protein (betaAPP) is proteolytically processed by two secretase activities to produce the pathogenic amyloid beta-peptide (Abeta). N-terminal cleavage is mediated by beta-secretase (BACE) whereas C-terminal intramembraneous cleavage is exerted by the presenilin (PS) gamma-secretase complex. The Abeta-generating,gamma-secretase cleavage principally occurs after amino acid 40 or 42 and results in secretion of A/beta-(1-40) or Abeta-(1-42). Upon overexpression of BACE in cultured cells we unexpectedly noticed a reduction of secreted Abeta-(1-40/ 42). However, mass spectrometry revealed a truncated Abeta species, which terminates at amino acid 34 (Abeta-(1-34)) suggesting an alternative gamma- secretase cut. Indeed, expression of a loss-of-function variant of PS1 inhibited not only the production of Abeta-(1-40) and Abeta-(1-42) but also that of Abeta-(1-34). However, expression levels of BACE correlate with the amount of Abeta-(1-34), and Abeta(1-34) is produced at the expense of Abeta-(1-40) and Abeta(1-42). Since this suggested that BACE is involved in a C- teriminal truncation of Abeta, we incubated purified BACE with Abeta-(1-40) in vitro. Under these conditions Abeta-(1-34) was generated. Moreover, when conditioned media containing Abeta- (1-40) and Abeta-(1-42) were incubated with cells expressing a loss-of-function PS1 variant together with BACE, Abeta-(1-34) was efficiently produced in vivo. These data demonstrate that an apparently gamma-secretase-dependent Abeta derivative is produced after the generation of the non-truncated Abeta via an additional and unexpected activity of BACE.

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Sprache(n): eng - English
 Datum: 2003-02-21
 Publikationsstatus: Erschienen
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 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: eDoc: 41752
ISI: 000181129400009
 Art des Abschluß: -

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Titel: Journal of Biological Chemistry
  Alternativer Titel : J. Biol. Chem.
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 278 (8) Artikelnummer: - Start- / Endseite: 5531 - 5538 Identifikator: ISSN: 0021-9258