Selective Modulation of Aβ42 Production in Alzheimers Disease: Non-Steroidal Anti-Inflammatory Drugs and Beyond
The amyloid-β (Aβ) peptides and in particular the longer, highly amyloidogenic isoform Aβ42 are believed by many to be the central disease-causing agents in Alzheimers disease (AD). Consequently, academic and pharmaceutical laboratories have focused on elucidating the mechanisms of Aβ production and developing strategies to diminish Aβ formation for treatment or prevention of AD. The most substantial advances have been made with respect to inhibitors of the γ-secretase enzyme, which catalyzes the final step in the generation of Aβ from the amyloid precursor protein (APP). Highly potent γ-secretase inhibitors which suppress production of all Aβ peptides are available today. However, due to the promiscuous substrate specificity of γ-secretase and its essential role in the NOTCH signaling pathway overt mechanismbased toxicity has been observed in preclinical studies of γ-secretase inhibitors. For that reason, specific blockage of Aβ42 production might be preferable over non-discriminatory γ-secretase inhibition but small molecule inhibitors of Aβ42 production have remained elusive until recently. This has changed with the discovery that certain non-steroidal antiinflammatory drugs (NSAIDs) including ibuprofen possess preferential Aβ42-lowering activity. These compounds seem to offer a window of modulation where Aβ42 production is potently inhibited whereas processing of the NOTCH receptor and other g-secretase substrates remains unaffected. The Aβ42-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 Aβ42-lowering compounds. Hopes are high that in the near future this will lead to the development of clinically viable compounds which selectively target Aβ42 as a key molecule in the pathogenesis of AD.
Keywords: amyloid precursor protein (APP), transmembrane domain (TMD), NOTCH signaling, NSAIDs, pro-inflammatory, Non-COX
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