Journal of Biological Chemistry
Volume 282, Issue 34, 24 August 2007, Pages 24504-24513
Journal home page for Journal of Biological Chemistry

Mechanisms of Signal Transduction
Insensitivity to Aβ42-lowering Nonsteroidal Anti-inflammatory Drugs and γ-Secretase Inhibitors Is Common among Aggressive Presenilin-1 Mutations*

https://doi.org/10.1074/jbc.M700618200Get rights and content
Under a Creative Commons license
open access

Aβ42-lowering nonsteroidal anti-inflammatory drugs (NSAIDs) constitute the founding members of a new class of γ-secretase modulators that avoid side effects of pan-γ-secretase inhibitors on NOTCH processing and function, holding promise as potential disease-modifying agents for Alzheimer disease (AD). These modulators are active in cell-free γ-secretase assays indicating that they directly target the γ-secretase complex. Additional support for this hypothesis was provided by the observation that certain mutations in presenilin-1 (PS1) associated with early-onset familial AD (FAD) change the cellular drug response to Aβ42-lowering NSAIDs. Of particular interest is the PS1-ΔExon9 mutation, which provokes a pathogenic increase in the Aβ42/Aβ40 ratio and dramatically reduces the cellular response to the Aβ42-lowering NSAID sulindac sulfide. This FAD PS1 mutant is unusual as a splice-site mutation results in deletion of amino acids Thr291–Ser319 including the endoproteolytic cleavage site of PS1, and an additional amino acid exchange (S290C) at the exon 8/10 splice junction. By genetic dissection of the PS1-ΔExon9 mutation, we now demonstrate that a synergistic effect of the S290C mutation and the lack of endoproteolytic cleavage is sufficient to elevate the Aβ42/Aβ40 ratio and that the attenuated response to sulindac sulfide results partially from the deficiency in endoproteolysis. Importantly, a wider screen revealed that a diminished response to Aβ42-lowering NSAIDs is common among aggressive FAD PS1 mutations. Surprisingly, these mutations were also partially unresponsive to γ-secretase inhibitors of different structural classes. This was confirmed in a mouse model with transgenic expression of the PS1-L166P mutation, in which the potent γ-secretase inhibitor LY-411575 failed to reduce brain levels of soluble Aβ42. In summary, these findings highlight the importance of genetic background in drug discovery efforts aimed at γ-secretase, suggesting that certain AD mouse models harboring aggressive PS mutations may not be informative in assessing in vivo effects of γ-secretase modulators and inhibitors.

Cited by (0)

*

This work was supported by an Emmy Noether Phase II grant (WE 2561/1-3) from the Deutsche Forschungsgemeinschaft (to S. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3 and Tables I and II.

This article was selected as a Paper of the Week.

1

Current address: Dept. of Neuropathology, Heinrich-Heine-University, 40225 Düsseldorf, Germany.