A new way APP mismetabolism can lead to Alzheimer's disease

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/e‐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.Figure 1. Pathogenic mutations in APP. Amino acids highlighted in red are known to be pathogenic. The newly discovered mutation affecting cleavage at the β′‐site is highlighted in grey. Cleavage sites for different secretases are indicated. Note that the γ‐secretase cleaves APP at multiple sites starting between amino acid 718 and 719 and then proceeding …