title: Comparable dimerization found in wildtype and familial Alzheimer's disease amyloid precursor protein mutants.
abstract: Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder marked by memory impairment and cognitive deficits. A major component of AD pathology is the accumulation of amyloid plaques in the brain, which are comprised of amyloid beta (Aβ) peptides derived from the amyloidogenic processing of the amyloid precursor protein (AβPP) by β- and γ-secretases. In a subset of patients, inheritance of mutations in the AβPP gene is responsible for altering Aβ production, leading to early onset disease. Interestingly, many of these familial mutations lie within the transmembrane domain of the protein near the GxxxG and GxxxA dimerization motifs that are important for transmembrane interactions. As AβPP dimerization has been linked to changes in Aβ production, it is of interest to know whether familial AβPP mutations affect full-length APP dimerization. Using bimolecular fluorescence complementation (BiFC), blue native gel electrophoresis, and live cell chemical cross-linking, we found that familial Alzheimer's disease (FAD) mutations do not affect full-length AβPP dimerization in transfected HEK293 and COS7 cells. It follows that changes in AβPP dimerization are not necessary for altered Aβ production, and in FAD mutations, changes in Aβ levels are more likely a result of alternative proteolytic processing.
authors.affiliation: Department of Medicine Graduate Program in Molecular Medicine, Boston University School of Medicine 72 East Concord Street, K-304, Boston, MA, 02118, USA.
authors.forename: Pauline Pl
authors.initials: PP
authors.lastname: So
authors.forename: Christina E
authors.initials: CE
authors.lastname: Khodr
authors.forename: Ci-Di
authors.initials: CD
authors.lastname: Chen
authors.forename: Carmela R
authors.initials: CR
authors.lastname: Abraham
keywords: Alzheimer’s disease; amyloid beta-peptides; amyloid-β precursor protein; familial Alzheimer’s disease; protein dimerization