APP processing and Aβ generation and mutations that affect β-secretase cleavage. A. APP is a Type-I membrane protein that is sequentially cleaved by two aspartic proteases to generate Aβ. First, the β-secretase enzyme cuts APP (1) to create the N-terminus of Aβ. Two APP fragments are produced: membrane-bound C99 and secreted sAPPβ ectodomain. Second, C99 is cleaved by the γ-secretase enzyme (2) to generate the C-terminus of Aβ. Aβ is then released into the lumen of the endosome and secreted into the extracellular medium. An intracellular domain, C59, is also produced. B. The amino acids in and around the Aβ domain of APP are represented as blue circles. Amino acids that affect β-secretase processing of APP in humans are green circles, within which the wild-type residue is identified by the single-letter amino acid code. The K670N/M671L (Swedish) and A673V mutations cause FAD by increasing β-secretase cleavage and Aβ production, while the A673T mutation protects against AD by doing the opposite. All three mutations occur at or within one amino acid of the β-secretase cleavage site. Scissors indicate cleavage sites of the various secretases.