Gleevec inhibits β-amyloid production but not Notch cleavage
作者： W. J. Netzer , F. Dou , D. Cai , D. Veach , S. Jean
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摘要: Amyloid-β (Aβ) peptides, consisting mainly of 40 and 42 aa (Aβ40 Aβ42, respectively), are metabolites the amyloid precursor protein believed to be major pathological determinants Alzheimer's disease. The proteolytic cleavages that form Aβ N C termini catalyzed by β-secretase γ-secretase, respectively. Here we demonstrate γ-secretase generation in an N2a cell-free system is ATP dependent. In addition, Abl kinase inhibitor imatinib mesylate (Gleevec, or STI571), which targets ATP-binding site several other tyrosine kinases, potently reduces production intact cells. Both STI571 a related compound, 2, also reduce rat primary neuronal cultures vivo guinea pig brain. does not inhibit γ-secretase-catalyzed S3 cleavage Notch-1. Furthermore, its inhibition were demonstrated occur similar extents both Abl-/- WT mouse fibroblasts, indicating effect on involve kinase. efficacy reducing without affecting Notch-1 may prove useful as basis for developing novel therapies
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