FAD-linked mutations in presenilin 1 alter the length of Aβ peptides derived from βAPP transmembrane domain mutants

γ-Secretase is an enzymatic activity responsible for the final cleavage of the amyloid precursor protein leading to the production of the amyloid β-peptide (Aβ). γ-Secretase is likely an aspartyl protease, since its activity can be inhibited by both pepstatin and active-site directed aspartyl protease inhibitors. Recent work has indicated that presenilins 1 and 2 may actually be the γ-secretase enzymes. Presenilin (PS) mutations, which lead to an increase in the production of a longer form of Aβ, are also the most common cause of familial Alzheimer's disease (FAD). Therefore, in an attempt to better characterize the substrate preferences of γ-secretase, we performed experiments to determine how FAD-linked mutations in PS1 would affect the generation of Aβ peptides from full length precursor substrates that we have previously demonstrated to be proteolytically cleaved at alternative sites and/or by enzymatic activities that are pharmacologically distinct. Presenilin mutations increased the production of Aβ peptides from sites distal to the primary cleavage site ('longer' peptides) and in several cases also decreased production of 'shorter' peptides. These results support a model in which the FAD-linked mutants subtly alter the conformation of the γ-secretase complex to favor the production of long Aβ.