Gleevec inhibits -amyloid production but not Notch cleavage

Amyloid(A ) peptides, consisting mainly of 40 and 42 aa (A 40 and A 42, 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 A N and C termini are catalyzed by -secretase and -secretase, respectively. Here we demonstrate that -secretase generation of A 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 A production in the N2a cell-free system and in intact N2a cells. Both STI571 and a related compound, inhibitor 2, also reduce A production in rat primary neuronal cultures and in vivo in guinea pig brain. STI571 does not inhibit the -secretase-catalyzed S3 cleavage of Notch-1. Furthermore, production of A 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 A production does not involve Abl kinase. The efficacy of STI571 in reducing A without affecting Notch-1 cleavage may prove useful as a basis for developing novel therapies for Alzheimer’s disease.