PMID- 12809514
OWN - NLM
STAT- MEDLINE
DCOM- 20030731
LR  - 20091119
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 42
IP  - 24
DP  - 2003 Jun 24
TI  - Catalytic site-directed gamma-secretase complex inhibitors do not discriminate 
      pharmacologically between Notch S3 and beta-APP cleavages.
PG  - 7580-6
AB  - The generation of gamma-secretase inhibitors which block the release of 
      beta-amyloid peptide (Abeta) has long been an attractive therapeutic avenue for 
      treatment or prevention of Alzheimer's disease (AD). Such inhibitors would reduce 
      levels of Abeta available for aggregation into toxic assemblies that lead to the 
      plaque pathology found in affected brain tissue. Cumulative evidence suggests 
      that the S3 cleavage of Notch is also dependent on presenilins (PS) and is 
      carried out by the multimeric PS-containing gamma-secretase complex. It is 
      therefore possible that Notch function could be affected by gamma-secretase 
      inhibitors. To assess the relationship between the cleavage of these substrates 
      in the same system, Western blot cleavage assays have been established using a 
      human cell line stably expressing both the beta-amyloid precursor protein 
      (beta-APP) and the truncated Notch1 receptor fragment NotchDeltaE. Thus, a direct 
      correlation may be made, following inhibitor treatment, of the decrease in the 
      levels of the cleavage products, Abeta peptide and the Notch intracellular domain 
      (NICD), as well as the increase in stabilized levels of both substrates. This 
      analysis has been performed with a range of selected gamma-secretase inhibitors 
      from six distinct structural classes. Changes in all four species usually occur 
      in concert and with remarkably good agreement. A significant cleavage window is 
      not clearly apparent in any case. Thus, these Notch and beta-APP cleavages cannot 
      be dissected apart easily since they show the same pharmacological profile of 
      inhibition. Whether this translates into proportionally reduced Notch signaling 
      in vivo, however, remains to be seen.
FAU - Lewis, Huw D
AU  - Lewis HD
AD  - Department of Biochemistry and Molecular Biology, The Neuroscience Research 
      Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park, Harlow, Essex, 
      UK.
FAU - Perez Revuelta, Blanca I
AU  - Perez Revuelta BI
FAU - Nadin, Alan
AU  - Nadin A
FAU - Neduvelil, Joe G
AU  - Neduvelil JG
FAU - Harrison, Timothy
AU  - Harrison T
FAU - Pollack, Scott J
AU  - Pollack SJ
FAU - Shearman, Mark S
AU  - Shearman MS
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Carbamates)
RN  - 0 (Dipeptides)
RN  - 0 (L 685458)
RN  - 0 (Membrane Proteins)
RN  - 0 (Protease Inhibitors)
RN  - 0 (Receptors, Notch)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
SB  - IM
MH  - Alzheimer Disease/enzymology
MH  - Amyloid Precursor Protein Secretases
MH  - Amyloid beta-Protein Precursor/*metabolism
MH  - Aspartic Acid Endopeptidases
MH  - Blotting, Western
MH  - Carbamates/analysis/chemistry
MH  - Catalytic Domain
MH  - Cell Line
MH  - Dipeptides/analysis/chemistry
MH  - Dose-Response Relationship, Drug
MH  - Endopeptidases/chemistry/*metabolism
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Membrane Proteins/chemistry/*metabolism
MH  - Molecular Mimicry
MH  - Protease Inhibitors/chemistry/*pharmacology
MH  - Protein Structure, Tertiary
MH  - Receptors, Notch
MH  - Signal Transduction
EDAT- 2003/06/18 05:00
MHDA- 2003/08/02 05:00
CRDT- 2003/06/18 05:00
PHST- 2003/06/18 05:00 [pubmed]
PHST- 2003/08/02 05:00 [medline]
PHST- 2003/06/18 05:00 [entrez]
AID - 10.1021/bi034310g [doi]
PST - ppublish
SO  - Biochemistry. 2003 Jun 24;42(24):7580-6. doi: 10.1021/bi034310g.