Gleevec inhibits β-amyloid production but not Notch cleavage Journal Article
| Authors: | Netzer, W. J.; Dou, F.; Cai, D.; Veach, D.; Jean, S.; Li, Y.; Bornmann, W. G.; Clarkson, B.; Xu, H.; Greengard, P. |
| Article Title: | Gleevec inhibits β-amyloid production but not Notch cleavage |
| Abstract: | Amyloid-β (Aβ) peptides, consisting mainly of 40 and 42 aa (Aβ40 and Aβ42, 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 Aβ N and C termini are catalyzed by β-secretase and γ-secretase, respectively. Here we demonstrate that γ-secretase generation of Aβ 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 Aβ production in the N2a cell-free system and in intact N2a cells. Both STI571 and a related compound, inhibitor 2, also reduce Aβ production in rat primary neuronal cultures and in vivo in guinea pig brain. STI571 does not inhibit the γ-secretase-catalyzed S3 cleavage of Notch-1. Furthermore, production of Aβ 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 Aβ production does not involve Abl kinase. The efficacy of STI571 in reducing Aβ without affecting Notch-1 cleavage may prove useful as a basis for developing novel therapies for Alzheimer's disease. |
| Keywords: | controlled study; human cell; nonhuman; animals; mice; mice, knockout; animal tissue; cells, cultured; imatinib; carboxy terminal sequence; protein degradation; culture medium; cell line; animal model; membrane proteins; notch receptor; in vivo study; neurons; receptor, notch1; osmotic minipump; pyrimidines; animalia; transcription factors; cell culture; enzyme inhibitors; fibroblast; binding site; inhibition kinetics; rats; protein-tyrosine kinases; piperazines; adenosine triphosphate; drug protein binding; alzheimer disease; amyloid precursor protein; amyloid precursor protein secretases; gamma secretase; enzyme active site; receptors, cell surface; amyloid beta-protein; endopeptidases; amyloid beta protein; proto-oncogene proteins c-abl; genes, abl; guinea pig; binding kinetics; beta secretase; aspartic endopeptidases; guinea pigs; human; male; female; priority journal; article; sus scrofa; cavia porcellus |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 100 |
| Issue: | 21 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2003-10-21 |
| Start Page: | 12444 |
| End Page: | 12449 |
| Language: | English |
| DOI: | 10.1073/pnas.1534745100 |
| PUBMED: | 14523244 |
| PROVIDER: | scopus |
| PMCID: | PMC218777 |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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