Imatinib treatment and Aβ42 in humans

Alzheimers Dement. 2014 Oct;10(5 Suppl):S374-80. doi: 10.1016/j.jalz.2013.08.283. Epub 2013 Dec 10.

Abstract

Background: The first-line treatment in chronic myeloid leukemia (CML), imatinib, has been shown to decrease the production of amyloid-β (Aβ) in vitro and in animal studies. However, whether imatinib has this effect in humans is not known.

Methods: Plasma levels of Aβ42 were analyzed in sequential samples from CML patients treated with imatinib (n=51). The effect of imatinib on Aβ production was also investigated in human embryonic kidney 293 (HEK293) cells overexpressing the amyloid precursor protein (APP) with the Swedish mutation, in mouse primary cortical neurons and in human Down syndrome embryonic stem-cell-derived cortical neurons.

Results: Twelve months of imatinib treatment did not lower plasma Aβ42 levels in CML patients, and imatinib treatment did not lead to less Aβ42 production in any of the in vitro models whereas β- and γ-secretase inhibitors did.

Conclusion: These data question the previously described role of imatinib in inhibiting amyloidogenic APP processing and as a drug candidate for AD.

Keywords: Alzheimer's disease; Aβ42; CML; Imatinib; Plasma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / physiopathology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use
  • Cells, Cultured
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / physiopathology
  • Down Syndrome / drug therapy
  • Down Syndrome / physiopathology
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / physiology
  • Female
  • HEK293 Cells
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / blood
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Male
  • Mice
  • Neurons / drug effects
  • Neurons / physiology
  • Peptide Fragments / metabolism*
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use

Substances

  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Benzamides
  • Peptide Fragments
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • amyloid beta-protein (1-42)
  • Imatinib Mesylate
  • Amyloid Precursor Protein Secretases