γ-secretase modulation with Aβ42-lowering nonsteroidal anti-inflammatory drugs and derived compounds

The amyloid-beta (A beta) pepticles and specifically the highly amyloidogenic isoform A beta 42 appear to be key agents in the pathogenesis of familial and sporadic forms of Alzheimer's disease (AD). The final step in the generation of A beta from the amyloid precursor protein is catalyzed by the multiprotein complex gamma-secretase, which constitutes a prime drug target for prevention and therapy of the disease. However, highly potent gamma-secretase inhibitors that block formation of all A beta peptides have provoked troubling side effects in preclinical animal models of AD. This toxicity can be readily explained by the promiscuous substrate specificity of gamma-secretase and its essential role in the NOTCH signaling pathway. For that reason and because of the crucial role of A beta 42 in the pathogenesis of the disease, selective inhibition of A beta 42 production would seem to be a more promising alternative to complete inhibition of gamma-secretase activity. This theoretical concept:has edged much closer to clinical reality with the surprising finding that certain nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, and derived compounds display preferential A beta 42-lowering activity. In contrast to gamma-secretase inhibitors, these gamma-secretase modulators effectively suppress A beta 42 production while sparing processing of NOTCH and other gamma-secretase substrates. Although not fully resolved on the molecular level, the mechanism of action of A beta 42-lowering NSAIDs is independent of cyclooxygenase inhibition and most likely involves direct interaction with components of the gamma-secretase complex or its substrates. Current efforts to improve the pharmacological shortcomings of available gamma-secretase modulators will hopefully lead to the development of clinically useful A beta 42-lowering compounds in the near future. Copyright (c) 2006 S. Karger AG, Basel.