title: Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants.
abstract: BACKGROUND
  Amyloid precursor protein (APP) is enzymatically cleaved by gamma-secretase to form two peptide products, either Abeta40 or the more neurotoxic Abeta42. The Abeta42/40 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.
  
  
  CONCLUSIONS
  The dissociation constants are correlated to both the Abeta42/Abeta40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce Abeta production and Abeta42/Abeta40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and gamma-secretase components, potentially revealing a new class of gamma-secretase inhibitors.
authors.affiliation: Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada. pgorman@westwindpartners.ca
authors.forename: Paul M
authors.initials: PM
authors.lastname: Gorman
authors.forename: Sanguk
authors.initials: S
authors.lastname: Kim
authors.forename: Meng
authors.initials: M
authors.lastname: Guo
authors.forename: Roman A
authors.initials: RA
authors.lastname: Melnyk
authors.forename: Joanne
authors.initials: J
authors.lastname: McLaurin
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.forename: James U
authors.initials: JU
authors.lastname: Bowie
authors.forename: Avijit
authors.initials: A
authors.lastname: Chakrabartty
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D013548:Sweden
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)