Gleevec inhibits β-amyloid production but not Notch cleavage

doi:10.1073/pnas.1534745100

Gleevec inhibits β-amyloid production but not Notch cleavage

^*Fisher Center for Research on Alzheimer's Disease, Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021; and ^‡Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Contributed by Paul Greengard, July 25, 2003

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.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: greengd{at}mail.rockefeller.edu.
↵ † W.J.N, F.D., and D.C. contributed equally to this work.
↵ § Present address: Center for Neuroscience and Aging, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037.
Abbreviations: βAPP, β-amyloid precursor protein; sβAPP, soluble βAPP; Aβ, β-amyloid peptide; Aβn, n-aa β-amyloid peptide; βCTF, C-terminal fragment of βAPP cleaved by β-secretase; SELDI, surface enhanced laser desorption/ionization; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide.