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Am J Neurodegener Dis 2013;2(1):15-28

Original Article
Comparable dimerization found in wildtype and familial Alzheimer’s
disease amyloid precursor protein mutants

Pauline PL So, Christina E Khodr, Ci-Di Chen, Carmela R Abraham

Department of Medicine Graduate Program in Molecular Medicine and Department of Biochemistry, Boston University
School of Medicine, 72 East Concord Street, K-304, Boston, MA, 02118, USA

Received January 10, 2013; Accepted February 6, 2013; Epub March 8, 2013; Published March 18, 2013

Abstract: Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder marked by memory
impairment and cognitive defi-cits. A major component of AD pathology is the accumulation of amyloid plaques in the
brain, which are comprised of amyloid beta (Aβ) pep-tides 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. (AJND1301001)

Keywords: Alzheimer’s disease, amyloid-β precursor protein, familial Alzheimer’s disease, amyloid beta-peptides,
protein dimerization

Address correspondence to: Carmela R. Abraham, Boston University School of Medicine, 72 East Concord Street, K-
304, Boston, MA, 02118, USA. Phone: 617-638-4308; Fax: 617-638-5339; E-mail: cabraham@bu.edu