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 (Aß) peptides derived from the amyloidogenic processing of the amyloid precursor protein (AßPP) by ß- and γ-secretases. In a subset of patients, inheritance of mutations in the AßPP gene is responsible for altering Aß 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 AßPP dimerization has been linked to changes in Aß production, it is of interest to know whether familial AßPP 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 AßPP dimerization in transfected HEK293 and COS7 cells. It follows that changes in AßPP dimerization are not necessary for altered Aß production, and in FAD mutations, changes in Aß levels are more likely a result of alternative proteolytic processing.