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

Alzheimer's disease is characterized by accumulation of toxic β-amyloid (Aβ) in the brain and neuronal death. Several mutations in presenilin (PS1) and β-amyloid precursor protein (APP) associate with an increased Aβ42/40 ratio. Aβ42, a highly fibrillogenic species, is believed to drive Aβ aggregation. Factors shifting γ-secretase cleavage of APP to produce Aβ42 are unclear. We investigate the molecular mechanism underlying altered Aβ42/40 ratios associated with APP mutations at codon 716 and 717. Using FRET-based fluorescence lifetime imaging to monitor APP–PS1 interactions, we show that I716F and V717I APP mutations increase the proportion of interacting molecules earlier in the secretory pathway, resulting in an increase in Aβ generation. A PS1 conformation assay reveals that, in the presence of mutant APP, PS1 adopts a conformation reminiscent of FAD-associated PS1 mutations, thus influencing APP binding to PS1/γ-secretase. Mutant APP affects both intracellular location and efficiency of APP–PS1 interactions, thereby changing the Aβ42/40 ratio.