Mutations in amyloid precursor protein affect its interactions with presenilin/γ-secretase

Alzheimer's disease is characterized by accumulation of toxic beta-amyloid (AO) in the brain and neuronal death. Several mutations in presenilin (PS1) and beta-amyloid precursor protein (APP) associate with an increased A beta(42/40) ratio. A beta(42), a highly fibrillogenic species, is believed to drive A beta aggregation. Factors shifting gamma-secretase cleavage of APP to produce A beta(42) are unclear. We investigate the molecular mechanism underlying altered A beta(42/40) ratios associated with APP mutations at codon 716 and 717. Using FRET-based fluorescence lifetime imaging to monitor APP-PS1 interactions, we show that 1716F and V7171 APP mutations increase the proportion of interacting molecules earlier in the secretory pathway, resulting in an increase in Al generation. A PSI conformation assay reveals that, in the presence of mutant APP, PSI adopts a conformation reminiscent of FAD-associated PS1 mutations, thus influencing APP binding to PS1/gamma-secretase. Mutant APP affects both intracellular location and efficiency of APP-PS1 interactions, thereby changing the A beta(42/40) ratio. (C) 2009 Elsevier Inc. All rights reserved.