Gleevec inhibits beta-amyloid production but not Notch cleavage.
Amyloid-beta (Abeta) peptides, consisting mainly of 40 and 42 aa (Abeta40 and Abeta42, respectively), are metabolites of the amyloid precursor protein and are believed to be major pathological determinants of Alzheimer's disease. The proteolytic cleavages that form the Abeta N and C termini are catalyzed by beta-secretase and gamma-secretase, respectively. Here we demonstrate that gamma-secretase generation of Abeta in an N2a cell-free system is ATP dependent. In addition, the Abl kinase inhibitor imatinib mesylate (Gleevec, or STI571), which targets the ATP-binding site of Abl and several other tyrosine kinases, potently reduces Abeta production in the N2a cell-free system and in intact N2a cells. Both STI571 and a related compound, inhibitor 2, also reduce Abeta production in rat primary neuronal cultures and in vivo in guinea pig brain. STI571 does not inhibit the gamma-secretase-catalyzed S3 cleavage of Notch-1. Furthermore, production of Abeta and its inhibition by STI571 were demonstrated to occur to similar extents in both Abl-/- and WT mouse fibroblasts, indicating that the effect of STI571 on Abeta production does not involve Abl kinase. The efficacy of STI571 in reducing Abeta without affecting Notch-1 cleavage may prove useful as a basis for developing novel therapies for Alzheimer's disease.
Netzer
William J
WJ
Fisher Center for Research on Alzheimer's Disease, Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA..
Dou
Fei
F
Cai
Dongming
D
Veach
Darren
D
Jean
Stephanie
S
Li
Yueming
Y
Bornmann
William G
WG
Clarkson
Bayard
B
Xu
Huaxi
H
Greengard
Paul
P
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001549:Benzamides; D002460:Cell Line; D002478:Cells, Cultured; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016313:Genes, abl; D006168:Guinea Pigs; D000068877:Imatinib Mesylate; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors
D016229:Amyloid beta-Peptides; D001549:Benzamides; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C497763:Notch1 protein, rat; D010879:Piperazines; D011743:Pyrimidines; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse