Increase of Aβ42 generation by substitutions within TM2. A, the sequence of TM2 domain of WT PS1, WT PS2, and TM2 aa6/15 variant are shown. FAD-linked mutations found within TM2 domain are indicated. Substitutions in aa6/15 variant are underlined. B, stable PS1−/−/PS2−/− MEF pools expressing PS1 TM2 variants were transiently infected with a retrovirus expressing APPSwe. Conditioned medium was collected 48 h after infection, and the levels of secreted Aβ40 and Aβ42 peptides were measured by ELISA.