Gleevec inhibits β-amyloid production but not Notch cleavage Academic Article uri icon

Overview

MeSH Major

  • Amyloid beta-Peptides
  • Membrane Proteins
  • Piperazines
  • Pyrimidines
  • Receptors, Cell Surface
  • Transcription Factors

abstract

  • 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.

publication date

  • October 14, 2003

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC218777

Digital Object Identifier (DOI)

  • 10.1073/pnas.1534745100

PubMed ID

  • 14523244

Additional Document Info

start page

  • 12444

end page

  • 9

volume

  • 100

number

  • 21