First and Second Generation γ-Secretase Modulators (GSMs) Modulate Amyloid-β (Aβ) Peptide Production through Different Mechanisms

Abstract

Background: ␥-Secretase modulators (GSMs) hold potential as disease modifiers in Alzheimer disease; however, their mechanism of action is not completely understood. Results: Second generation in vivo active GSMs were described and shown to modulate A␤ production via a non-APP targeting mechanism, different from the NSAIDs class of GSMs. Conclusion: A growing class of second generation GSMs appears to target ␥-secretase and displays a different mechanism of action compared with first generation GSMs. Significance: The identification of in vivo active non-APP targeting second generation GSMs may facilitate the development of novel therapeutics against AD.

γ-Secretase Modulator (GSM) Photoaffinity Probes Reveal Distinct Allosteric Binding Sites on Presenilin

“…Given the structural similarities of these imidazole-based GSMs, it is surprising that such differential effects are observed in the presence of L458. Consistent with the subtle differences in binding profiles described above, E2012 and the RO imidazole GSMs also have slightly different A␤ profiles (22,23). Although both compounds reduce A␤42 and A␤40, E2012 increases A␤37 Ͼ A␤38, and RO-02 increases A␤38 Ͼ A␤37.…”

“…Although both compounds reduce A␤42 and A␤40, E2012 increases A␤37 Ͼ A␤38, and RO-02 increases A␤38 Ͼ A␤37. Subtle differences in A␤ profiles have also been reported among other imidazole GSMs (23). Further studies to understand the subtle differences in binding and A␤ profiles of these different imidazole GSMs are clearly warranted.…”

Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease

“…Binding to Plasma Proteins and Brain Tissue-Plasma protein and brain tissue binding was determined as described in Borgegard et al (43). In short, AZD3839 was added to mouse, guinea pig, and monkey plasma to a final concentration of 10 M. An aliquot was transferred to a dialysis plate with phosphate buffer on the other site and incubated for 18 h at 37°C.…”

“…Bioanalysis of in Vivo Samples-Bioanalysis was performed as previously described in Borgegard et al (43). Briefly, right brain hemisphere was homogenized in 2 volumes (w/v) of Ringer solution.…”

Initial Optimization of a New Series of γ-Secretase Modulators Derived from a Triterpene Glycoside

“…22,23 A recent report of three distinct pyrimidine-based GSMs showed reduction of both Aβ40 and Aβ42 in vitro but different effects on Aβ(37− 39), with some examples raising Aβ38 and some having no effect on Aβ38 production. 32 These "second generation" GSMs have achieved much higher activities toward Aβ42 reduction than NSAIDs, and several examples have shown efficacy and selectivity both in vitro and in vivo, supporting modulation of γ-secretase as an effective approach to decreasing toxic species of Aβ without preventing the processing of other proteins, including Notch. Thus, modulation of γ-secretase has great potential as a therapeutic approach for the treatment of Alzheimer's disease.…”