Netzer WJ, Bettayeb K, Sinha SC, Flajolet M, Greengard P, Bustos V. Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage. Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):1389-1394. Epub 2017 Jan 23 PubMed.

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  1. While it would be important news to find a way to selectively inhibit β-secretase cleavage of APP without also blocking cleavage of other substrates of this protease, the new report from Netzer and colleagues falls short of making this claim. There are no side-by-side comparisons in the same experiments showing the differential effect on APP, and these experiments were carried out under different conditions, using stable transfection for APP and transient transfection for two other β-secretase substrates, L1CAM and Sez6. For L1CAM and Sez6, only their CTF levels were examined, not the soluble ectodomains, the other products of cleavage by β-secretase. Soluble ectodomain levels would provide a more reliable readout of effects on β-secretase cleavage of substrates, as levels of CTF are dependent on the degree of production by β-secretase and degradation by γ-secretase.

    These points are important, because if imatinib affects β-secretase activity more broadly, then the compound does not work like the protective Icelandic mutation, and there would be no obvious therapeutic advantage over direct β-secretase inhibitors. Moreover, Netzer et al. did not look at arguably the most important other substrate for β-secretase from an AD therapeutic perspective—neuregulin. Potential toxic effects of β-secretase inhibitors through blocking critical neuregulin signaling are of critical concern as these compounds advance through clinical trials. 

    Beyond the question of the validity of the new findings, I am concerned about the claim in this new study that it does not conflict with their original report on the effects of imatinib on Aβ production (Netzer et al., 2003). In that previous study, the authors claimed, and showed some evidence, that imatinib blocked cleavage of APP, but not Notch, by γ-secretase.  They showed some results where APP CTF-β was increased by imatinib, an effect consistent with inhibition of γ-secretase.  We and others were unable to reproduce these results with imatinib (e.g., Fraering et al., 2005). Later, this same lab reported that the relevant target of imatinib was a protein they dubbed γ-secretase interacting protein (GSAP), which selectively affected γ-secretase processing of APP over Notch (He G et al., 2010). This role of GSAP was never validated, although many labs—especially in biopharma companies—tried hard to do so, as it would have been a promising drug target (e.g., Hussain et al., 2013). 

    Now Netzer et al. say that imatinib is selectively inhibiting β-secretase cleavage of APP without affecting cleavage of other β-secretase substrates, with insufficient results to support this claim.  My worry is that many other labs will now spend precious time trying to reproduce and build upon this work, taking away from the pursuit of more promising avenues of investigation.

    References:

    Netzer WJ, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann WG, Clarkson B, Xu H, Greengard P. Gleevec inhibits beta-amyloid production but not Notch cleavage. Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12444-9. PubMed.

    Fraering PC, Ye W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS. gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J Biol Chem. 2005 Dec 23;280(51):41987-96. PubMed.

    He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P. Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature. 2010 Sep 2;467(7311):95-8. PubMed.

    Hussain I, Fabrègue J, Anderes L, Ousson S, Borlat F, Eligert V, Berger S, Dimitrov M, Alattia JR, Fraering PC, Beher D. The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation. J Biol Chem. 2013 Jan 25;288(4):2521-31. PubMed.

    View all comments by Michael Wolfe

  2. The paper by Netzer and colleagues reports the results of their very interesting study describing the ability of imatinib mesylate (Gleevec) to lower Aβ levels. The authors show that Gleevec and inhibitors of BACE enzymatic activity likely function via different mechanisms because Gleevec and BACE inhibitor IV were found to have synergistic effects in lowering the levels of Aβ secreted from cells. The observation that Gleevec treatment resulted in production of the same proteolytic C-terminal fragments of APP as those generated from mutant APP bearing the protective mutation A673T suggests that Gleevec decreases the BACE-mediated processing of APP without interfering with its enzymatic activity per se. One of the major findings of this paper is that the observed effects were specific to APP. Notably, Gleevec treatment was permissive for BACE1 cleavage of the two other substrates tested, L1 and Sez6.

    These results are particularly promising since a major concern regarding the use of BACE inhibitors in the clinic is the potential for side effects arising from chronically blocking BACE cleavage of its numerous brain substrates. While the proposal that Gleevec sequesters APP away from BACE in the lysosomal compartment is plausible, it may be generic (i.e., favoring trafficking of proteins from the plasma membrane and endoplasmic reticulum to lysosomes). It will be important to test more BACE substrates before concluding that the Gleevec effect is absolutely specific for APP

    Another major advance described in this paper is the discovery of a compound related to Gleevec (DV2-103) that lacks the tyrosine kinase inhibitor properties but retains the ability to lower Aβ production by indirectly affecting APP processing by BACE. Unlike Gleevec, however, DV2-103 is able to cross the blood-brain barrier, accumulate in the brain, and significantly lower brain Aβ levels in a mouse model of Alzheimer’s disease. As it lacks tyrosine kinase inhibitor activity, DV2-103 might be predicted to cause fewer side effects than Gleevec. If DV2-103 has similar BACE substrate-sparing properties to Gleevec, its improved central nervous system availability makes it an extremely attractive proposition for further characterization as an Alzheimer’s disease therapeutic.

    View all comments by Jenny Gunnersen

  3. This is an interesting paper. I am looking forward to seeing more mechanistic characterization in the future, in particular using primary neurons and endogenous APP, but also regarding the mechanistic basis of the differential effect on different BACE substrates (SEZ6 and L1 versus APP). Additionally, it would be great if the authors could identify similar compounds, but with much lower IC50 values.

    View all comments by Stefan Lichtenthaler

  4. This is a very nice extended study concerning the effect of Gleevec on lowering Aβ generation. The authors provide convincing evidence that Gleevec inhibits APP-CTFβ production through a kinase-independent manner and that this requires an acidic environment. However, it is not fully revealed how Gleevec would inhibit APP-CTFβ production, but not the other BACE1 substrates such as Sez6 and L1CAM, since the mechanism for this inhibition is through trafficking to lysosomes. Membrane proteins such as APP and neuregulin-1 have similar cellular location patterns, and would be expected to be similarly inhibited. Animal studies may provide more insight into the mechanism and potential clinical use.

    View all comments by Riqiang Yan

  5. Please excuse my tardiness in posting, but I just noticed a comment made by Michael Wolfe, concerning experimental conditions in our paper, Netzer et al. Dr. Wolfe's statement that N2a cells expressing a stable transfection of APP 695 were compared to transiently transfected N2a cells expressing the APP-A673T AD protective mutation is incorrect. The cells were transiently transfected for both APP 695 or APP-A673T, as noted in the Figure 2C legend and in the text p.1390, right side column lines 5-6, as well as in Methods.

    View all comments by William Netzer

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