Selective modulation of Abeta42 production in Alzheimer's disease: non-steroidal anti-inflammatory drugs and beyond.

The amyloid-beta (Abeta) peptides and in particular the longer, highly amyloidogenic isoform Abeta42 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 Abeta production and developing strategies to diminish Abeta 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 Abeta from the amyloid precursor protein (APP). Highly potent gamma-secretase inhibitors which suppress production of all Abeta 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 Abeta42 production might be preferable over non-discriminatory gamma-secretase inhibition but small molecule inhibitors of Abeta42 production have remained elusive until recently. This has changed with the discovery that certain non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen possess preferential Abeta42-lowering activity. These compounds seem to offer a window of modulation where Abeta42 production is potently inhibited whereas processing of the NOTCH receptor and other gamma-secretase substrates remains unaffected. The Abeta42-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 Abeta42-lowering compounds. Hopes are high that in the near future this will lead to the development of clinically viable compounds which selectively target Abeta42 as a key molecule in the pathogenesis of AD.