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Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2003 Aug 15; Vol. 278 (33), pp. 30748-54. Date of Electronic Publication: 2003 May 31. - Publication Year :
- 2003
-
Abstract
- Epidemiological studies indicate that long term use of nonsteroidal anti-inflammatory drugs (NSAIDs) confers protection from Alzheimer's disease, and some NSAIDs were shown to specifically decrease production of the amyloidogenic Abeta42 peptide, most likely by direct modulation of gamma-secretase activity. In contrast to gamma-secretase inhibitors, Abeta42-lowering NSAIDs do not impair S3 cleavage in the NOTCH receptor and release of the NOTCH intracellular domain, a finding with conceptual implications for the development of safer drugs targeting Abeta production through gamma-secretase modulation. Intramembrane cleavage and release of an intracellular signaling domain has recently been demonstrated in a number of additional gamma-secretase substrates. We now show in cell-based assays that intramembrane cleavage of APP and ErbB-4 receptor is not impaired by the Abeta42-lowering NSAIDs, sulindac sulfide and ibuprofen. Generation of the APP intracellular domain (AICD) was further not inhibited in a cell-free assay at concentrations far exceeding those effective in reducing Abeta42 production. Closer inspection of AICD signaling showed that stabilization of the AICD peptide by FE65 and AICD-mediated transcription were also retained at Abeta42-lowering concentrations. These results demonstrate that S3-like/intramembrane cleavage is preserved by Abeta42-lowering NSAIDs in at least three substrates of gamma-secretase APP, ErbB-4, and NOTCH and underline the striking specificity by which these drugs target Abeta42 production.
- Subjects :
- Amino Acid Sequence
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor chemistry
Amyloid beta-Protein Precursor genetics
Animals
Aspartic Acid Endopeptidases
CHO Cells
Cricetinae
Endopeptidases metabolism
ErbB Receptors chemistry
Humans
In Vitro Techniques
Membrane Proteins chemistry
Membrane Proteins metabolism
Protein Structure, Tertiary
Receptor, ErbB-4
Receptor, Notch1
Signal Transduction drug effects
Transcription, Genetic drug effects
Amyloid beta-Peptides metabolism
Amyloid beta-Protein Precursor metabolism
Anti-Inflammatory Agents, Non-Steroidal pharmacology
ErbB Receptors metabolism
Peptide Fragments metabolism
Receptors, Cell Surface
Signal Transduction physiology
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 278
- Issue :
- 33
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12777371
- Full Text :
- https://doi.org/10.1074/jbc.M304824200