FIGURE 7: Mechanism of APP FAD mutations. (A) Model depicting the shift in the Aβ40 and Aβ42 product lines by APP FAD mutations thereby causing relative increases in the generation of the longer Aβ42 species. Yellow asterisk indicates a FAD mutation. (B) Product line usage is governed by interactions with the S2´ enzyme subsite of γ-secretase. Sterically demanding aromatic amino acids at the P2´ position of C99 such as in the synthetic M51F mutant clash with the S2´ subsite of the Aβ40-line. (C) Pathway block by a clash of the aromatic P2´ with the S2´ subsite of the Aβ40-line in the FAD-associated I45F mutant causes a shift to the Aβ42-product line. Since this mutant does not alter the initial ε-site cleavage, Aβ42 is most likely generated from Aβ46.