Selective modulation of Aβ42 production in Alzheimer's disease:: Non-steroidal anti-inflammatory drugs and beyond

The amyloid-beta (A beta) peptides and in particular the longer, highly amyloidogenic isoform A beta 42 are believed by many to be the central disease-causing agents in Alzheimer's disease (AD). Consequently, academic and pharmaceutical laboratories have focused on elucidating the mechanisms of A beta production and developing strategies to diminish A beta formation for treatment or prevention of AD. The most substantial advances have been made with respect to inhibitors of the gamma-secretase enzyme, which catalyzes the final step in the generation of A beta from the amyloid precursor protein (APP). Highly potent gamma-secretase inhibitors which suppress production of all A beta peptides are available today. However, due to the promiscuous substrate specificity of gamma-secretase and its essential role in the NOTCH signaling pathway overt mechanism-based toxicity has been observed in preclinical studies of gamma-secretase inhibitors. For that reason, specific blockage of A beta 42 production might be preferable over non-discriminatory gamma-secretase inhibition but small molecule inhibitors of A beta 42 production have remained elusive until recently. This has changed with the discovery that certain non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen possess preferential A beta 42-lowering activity. These compounds seem to offer a window of modulation where A beta 42 production is potently inhibited whereas processing of the NOTCH receptor and other gamma-secretase substrates remains unaffected. The A beta 42-lowering activity of NSAIDs is not related to inhibition of cyclooxygenases and can be dissociated from the anti-inflammatory properties of this class of drugs. Ongoing efforts concentrate on uncovering the mechanism of action and improving potency and brain permeability of A beta 42-lowering compounds. Hopes are high that in the near future this will lead to the development of clinically viable compounds which selectively target A beta 42 as a key molecule in the pathogenesis of AD.