. Substrate-targeting gamma-secretase modulators. Nature. 2008 Jun 12;453(7197):925-9. PubMed.


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  1. The recent report by Kukar et al. provides compelling evidence that some GSMs can modulate γ-secretase activity by binding the APP-CTF. The authors propose that the binding of GSMs to the APP-CTF induces conformational changes in the PS1/γ-secretase when the GSM-bound substrate enters the complex. As pointed out by Golde and colleagues, these exciting new findings nicely support our previous studies (Tesco et al., 2005) showing that the APPV715F substitution in the APP transmembrane domain mimics the effects of Aβ42-lowering NSAIDs, by reducing the ratio of Aβ42:Aβ40. This same substitution affected AICD production and PS1 conformation in a similar way to that of NSAIDs. These data suggested that the Aβ transmembrane domain might serve as a target for γ-secretase modulation.

    Phenylalanine-scanning mutagenesis of the APP transmembrane domain (TMD) had previously shown that APPV715F substitution shifts Aβ cleavage toward the production of the less fibrillogenic species Aβ38, while decreasing levels of Aβ40 and even more dramatically, levels of Aβ42 (Lichtenthaler et al., 1999). We also found that the APPV715F substitution does not affect AICD production, but significantly increases the distance between the N- and C-termini of PS1, as assessed by FLIM analysis. The transmembrane domain of APP has been postulated to adopt an α-helix (Lichtenthaler et al., 1999; Qi-Takahara et al., 2005).

    Since amino acid substitutions in the APP transmembrane domain may change its helical conformation, in the discussion section of our paper, we hypothesized that amino acid substitutions in the TMD of APP can produce a change in PS1 conformation, e.g., the APPV715F substitution induces an Aβ1-38-favoring conformation that shifts γ-secretase cleavage away from Aβ42 production. Accordingly, we suggested that the Aβ42-lowering NSAIDs may not necessarily target the PS1/γ-secretase complex, but instead bind to the transmembrane portion of APP, altering its helical conformation, which, in turn, alters the conformation of the PS1/γ-secretase complex. In the conclusion of our paper we suggested “that an allosteric modulation of γ-secretase shifting Aβ generation toward the less fibrillogenic Aβ1-38 may be achieved by small compounds targeting not only PS1 and/or other components of the γ-secretase complex, but also APP.” The excellent new study from Kukar et al. provides exciting new data clearly supporting this hypothesis.


    . APP substitutions V715F and L720P alter PS1 conformation and differentially affect Abeta and AICD generation. J Neurochem. 2005 Oct;95(2):446-56. PubMed.

    . Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3053-8. PubMed.

    . Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci. 2005 Jan 12;25(2):436-45. PubMed.

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