Abstract
The amyloid hypothesis has yielded a series of well-validated candidate drug targets with potential for the treatment of Alzheimer disease (AD). Three proteases that are involved in the processing of amyloid precursor protein—α-secretase, β-secretase and γ-secretase—are of particular interest as they are central to the generation and modulation of amyloid-β peptide and can be targeted by small compounds in vitro and in vivo. Given that these proteases also fulfill other important biological roles, inhibiting their activity will clearly be inherently associated with mechanism-based toxicity. Carefully determining a suitable therapeutic window and optimizing the selectivity of the drug treatments towards amyloid precursor protein processing might be ways of overcoming this potential complication. Secretase inhibitors are likely to be the first small-molecule therapies aimed at AD modification that will be fully tested in the clinic. Success or failure of these first-generation AD therapies will have enormous consequences for further drug development efforts for AD and possibly other neurodegenerative conditions.
Key Points
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α-Secretase, β-secretase and γ-secretase are proteases that control the production of amyloid-β (Aβ) in the brain
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The secretases represent the most promising drug targets for Alzheimer disease therapies
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The α-secretase activity is mediated by a series of membrane-bound proteases, further research is needed to identify which of these proteases are most important for processing amyloid precursor protein
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β-Secretase and γ-secretase research has progressed enormously and compounds designed to attenuate their activity are in clinic trials
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The current trials test only whether elimination or attenuating Aβ in moderate to advanced AD could be beneficial
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A real test of the amyloid hypothesis will require drug testing at earlier stages of the disease
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Acknowledgements
This work was supported by a NIH/NIA grant (number AG25531) to T. Golde. B. De Strooper was supported by an Artificial SynApse (IWT-ASAP) grant, the Federal Office for Scientific Affairs, Belgium (IUAP P6/43), a Methusalem grant from the Flemish Government and a grant from the European Union (MEMOSAD, F2-2007-200611). R. Vassar received support from the NIH (grant numbers: P01 AG021184, R01 AG022560 and R01 AG030142), the Alzheimer's Association and the MetLife Foundation.
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B. De Strooper has received honoraria from Eisai, Eli Lilly, EnVivo, Johnson & Johnson and Probiodrug for consulting and has received research funding from Eli Lilly, EnVivo and Johnson & Johnson. He also holds the following European patent (EP) applications (EP 00200671.6, EP 01201015.3, EP 01202228.1, EP 02078915.2, EP 04106516.0, EP 05107454.0, EP 06120346.9, EP 07106482.8, EP 08063269, EP 09053985) with the Flanders institute for Biotechnology. T. Golde holds one patent application (WO0178721) with the Mayo Clinic. R. Vasser declares no competing interests.
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De Strooper, B., Vassar, R. & Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6, 99–107 (2010). https://doi.org/10.1038/nrneurol.2009.218
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DOI: https://doi.org/10.1038/nrneurol.2009.218
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