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.
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.
Weggen
Sascha
S
Department of Neurosciences, University of California San Diego, La Jolla, California 92093, USA. sweggen@ucsd.edu
Eriksen
Jason L
JL
Sagi
Sarah A
SA
Pietrzik
Claus U
CU
Golde
Todd E
TE
Koo
Edward H
EH
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases; D016466:CHO Cells; D006224:Cricetinae; D010450:Endopeptidases / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D066247:Receptor, ErbB-4; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D010446:Peptide Fragments; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human