Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease that causes progressive loss of cognitive functions, leading to dementia. Two types of lesions are found in AD brains: neurofibrillary tangles and senile plaques. The latter are composed mainly of the β-amyloid peptide (Aβ) generated by amyloidogenic processing of the amyloid precursor protein (APP). Several studies have suggested that dimerization of APP is closely linked to Aβ production. Nevertheless, the mechanisms controlling APP dimerization and their role in APP function are not known. Here we used a new luciferase complementation assay to analyze APP dimerization and unravel the involvement of its three major domains: the ectodomain, the transmembrane domain and the intracellular domain. Our results indicate that within cells full-length APP dimerizes more than its α and β C-terminal fragments, confirming the pivotal role of the ectodomain in this process. Dimerization of the APP transmembrane (TM) domain has been reported to regulate processing at the γ-cleavage site. We show that both non-familial and familial AD mutations in the TM GXXXG motifs strongly modulate Aβ production, but do not consistently change dimerization of the C-terminal fragments. Finally, we found for the first time that removal of intracellular domain strongly increases APP dimerization. Increased APP dimerization is linked to increased non-amyloidogenic processing.
Highlights
The amyloid precursor protein (APP) is a ubiquitously expressed type 1 transmembrane protein [1,2]
In contrast to b-amyloid peptide (Ab) production, dimerization is not altered in familial AD cases (FAD) mutants [27], challenging the hypothesis that dimerization is involved in amyloidogenic processing
The split luciferase assays we developed appeared as a very sensitive and reliable tool to decipher the mechanisms of APP dimerization in cells
Summary
The amyloid precursor protein (APP) is a ubiquitously expressed type 1 transmembrane protein [1,2]. APP undergoes proteolysis via two distinct pathways known as the amyloidogenic and the nonamyloidogenic pathways. APP processing is initiated by the shedding of the large ectodomain by either an a-secretase (nonamyloidogenic pathway) or the b-secretase BACE1 APP b-cleavage generates a membrane-anchored b Cterminal fragment (bCTF or C99), which is further cleaved by the c-secretase complex to generate the Ab peptides. The 40 and 42 amino acids Ab isoforms (Ab40 and Ab42, respectively) are the major constituents of the senile plaques, a typical lesion found in the brain of patients with Alzheimer’s disease (AD) [4]. Mutations responsible for inherited or familial AD cases (FAD) are located in the APP or presenilin genes (PS1 and PS2). The presenilin proteins are the catalytic subunits of the c-secretase. AD mutations typically result in an increased Ab42/Ab40 ratio [2]. Imbalanced production of Ab, along with its aggregation and accumulation in the brain, may play a critical role in the onset and progression of AD [5]
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