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Amyloid precursor protein (APP) is a transmembrane protein, which is sequentially cleaved at several sites by different enzymes. Cleavage leads to the production of different Aβ (β amyloid) species, which—when overproduced and aggregated—are a major cause of Alzheimer's disease.
The main cleavage sites in APP are the β‐ and γ/ε‐sites mediated by the respective secretases (Fig 1). Importantly, mutations in APP and the presenilins have been shown to cause Alzheimer's disease by a remarkable number of mechanisms. Now, it seems there is one at a previously underestimated site.
APP gene duplications and Down syndrome seem to simply cause more flux through the processing pathway by APP gene dose (Rovelet‐Lecrux et al, 2006), the London series of mutations and presenilin mutations increase the proportion of long Aβ species by marginally altering the production from the γ‐secretase cleavage (Scheuner et al, 1996), and the Flemish and similar Alzheimer causing mutations appear to reduce flux through the competing α‐secretase pathway (De Jonghe et al, 1998). Perhaps most famously, the Swedish mutation increased the flux through...