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Title: | Analysis by a highly sensitive split luciferase assay of the regions involved in APP dimerization and its impact on processing | Authors: | Decock, Marie El Haylani, Laetitia Stanga, Serena DEWACHTER, Ilse Octave, Jean-Noël Smith, Steven O Constantinescu, Stefan N Kienlen-Campard, Pascal |
Issue Date: | 2015 | Publisher: | WILEY | Source: | FEBS open bio, 5 (1) , p. 763 -773 | 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. | Keywords: | Alzheimer disease;APP;Dimerization;GXXXG motifs;Amyloid beta peptide;Split luciferase | Document URI: | http://hdl.handle.net/1942/30269 | ISSN: | 2211-5463 | e-ISSN: | 2211-5463 | DOI: | 10.1016/j.fob.2015.09.002 | ISI #: | 000366999300093 | Rights: | 2015 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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Decock_et_al-2015-FEBS_Open_Bio.pdf | Published version | 2.25 MB | Adobe PDF | View/Open |
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