Gleevec inhibits β-amyloid production but not Notch cleavage

Abstract

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.

Modulation of γ-secretase specificity using small molecule allosteric inhibitors

“…This may reflect subtle variations between the cellular and in vitro conformations of ␥-secretase. Nevertheless, the cell-based studies confirmed that CS-1 maintains a preference for inhibition of the ␥-secretase mediated production of A␤42 over A␤40 or A␤38, which is distinct from previously reported GSMs (17) and inhibitors (14,15,18).…”

“…Furthermore, these coumarin-dimer compounds similarly affect ␥-secretase activity for A␤40 and A␤38 production and lack the interconnected effect witnessed with the GSMs in which decreased A␤42 resulted in increased A␤38 generation, and vice versa (17). Therefore, these AGSIs represent a class of inhibitors that are distinct from the GSMs (12,17) as well as previously reported GSIs (14,15,18). It is noteworthy to point out that coumarin-dimer based compounds have been reported to be active against HIV integrase (32) and human NAD(P)H:quinine oxidoreductase-1 (33), as well as exhibit anticoagulant activity (34).…”

“…Subsequent studies have shown that these GSMs alter ␥-secretase cleavage preference by binding directly to the APP substrate (13). Other compounds that target ␥-secretase and preferentially inhibit A␤40 and A␤42 production over Notch1 processing have been reported (14,15), although the precise action mechanism of these molecules has not been established. Therefore, it is critical to develop a better understanding of the molecular basis of ␥-secretase specificity to facilitate the development of selective GSIs for the treatment of AD and other human disorders.…”

The anticancer drug imatinib induces cellular autophagy

“…Additionally, it has been shown that imatinib inhibits the growth of PDGF-R-mediated glioblastoma cells 8 and sensitizes glioma cells to radiation-induced apoptosis. 9 The observation that imatinib inhibits the b-amyloid production in a cell culture model, which could make the inhibitor a useful basis for the development of a novel therapy for Alzheimer's disease, 10 points to a possible implication of imatinib also in neurodegenerative diseases. In line with this, we previously published that imatinib can induce the cellular clearance of prion-infected cells from PrP Sc , the pathological isoform of the cellular prion protein (PrP c ), by activating its lysosomal degradation.…”

The Achilles heel of γ-secretase: can we contain Alzheimer's disease by reducing synthesis of β-amyloid?

“…Incidentally, the pharmacological agent that inhibits GSAP has already been synthesized; this agent is the anti-cancer drug imatinib (also known as STI571 or Gleevec), which has been previously shown (by the same group [6] ) to inhibit γ-secretase activity. The biotinylated derivative of imatinib was used to isolate GSAP.…”