التفاصيل البيبلوغرافية
| العنوان: |
Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation ; J. Biol. Chem. |
| المؤلفون: |
Fluhrer, R., Multhaup, G., Schlicksupp, A., Okochi, M., Takeda, M., Lammich, S., Willem, M., Westmeyer, G., Bode, W., Walter, J., Haass, C. |
| المصدر: |
Journal of Biological Chemistry |
| سنة النشر: |
2003 |
| المجموعة: |
Max Planck Society: MPG.PuRe |
| الوصف: |
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. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| Relation: |
http://hdl.handle.net/11858/00-001M-0000-0010-6C9B-4 |
| الاتاحة: |
http://hdl.handle.net/11858/00-001M-0000-0010-6C9B-4 |
| رقم الانضمام: |
edsbas.18A1DE84 |
| قاعدة البيانات: |
BASE |