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

gamma-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-beta (A beta) peptides. The A beta 42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several gamma-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related A beta production by targeting the APP. Here, we describe novel GSMs that are selective for A beta modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate A beta both in cell and cell-free systems as well as lower amyloidogenic A beta 42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a H-3-labeledAZGSManalog does not co-localize with APP but overlaps anatomically with a gamma-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for A beta modulation and have a different mechanism of action compared with the original class of GSMs described.