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♦ See referenced article, J. Biol. Chem. 2010, 285, 17798–17810
The generation of amyloid-β plaques in the brain represents one of the principal pathological hallmarks of Alzheimer disease (AD); these plaques are produced from the aggregation-prone 42-amino acid amyloid-β peptide, which is itself generated by the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Therefore, using γ-secretase modulators (GSMs) to lower Aβ42 levels by increasing production of the non-toxic species Aβ38 presents a hopeful approach toward AD treatment. In this Paper of the Week, Richard Page and colleagues analyzed different mutations within APP's transmembrane domain to examine the response to GSMs. They found that familial Alzheimer mutations known to increase Aβ42 production responded quite well to GSMs, thus suggesting a class of patients that should benefit from GSM therapies. However, their studies also revealed that levels of Aβ42 and Aβ38 were not always coupled and that GSMs could lower levels of other Aβ peptides like Aβ41 and Aβ39; these results argue against the idea that Aβ42 and Aβ38 exist in a simple precursor-product relationship. Furthermore, Page and colleagues also found that several mutations within the proposed GSM-binding site were still responsive to GSM treatment, indicating that the GSM mode of action is more complex than believed. Together, this study is significant as it challenges the current models of both γ-secretase and GSM activity.