Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants

Background: Amyloid precursor protein (APP) is enzymatically cleaved by gamma secretase to form two peptide products, either A beta 40 or the more neurotoxic A beta 42. The A beta 42/40 ratio is increased in many cases of familial Alzheimer's disease ( FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains. Results: Using synthetic peptides derived from the APP-TM domain, we show that this segment is capable of forming stable transmembrane dimers. A model of a dimeric APP-TM domain reveals a putative dimerization interface, and interestingly, majority of FAD mutations in APP are localized to this interface region. We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers. Conclusion: The dissociation constants are correlated to both the A beta 42/A beta 40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce A beta production and A beta 42/A beta 40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma- secretase components, potentially revealing a new class of gamma-secretase inhibitors.