NDLI: Differential Regulation of Amyloid Precursor Protein/Presenilin 1 Interaction during Ab40/42 Production Detected Using Fusion Constructs

Content Provider	PubMed Central
Author	Sato, Naoyuki Okochi, Masayasu Shinohara, Mitsuru Thinakaran, Gopal Takeda, Shuko Fukumori, Akio Shinohara-noma, Motoko Mari, Mori-ueda Hamada, Hizuki Takeda, Masatoshi Rakugi, Hiromi Morishita, Ryuichi
Editor	Forloni, Gianluigi
Copyright Year	2012
Abstract	Beta amyloid peptides (Aβ) play a key role in the pathogenesis of Alzheimer disease (AD). Presenilins (PS) function as the catalytic subunits of γ-secretase, the enzyme that releases Aβ from ectodomain cleaved amyloid precursor protein (APP) by intramembrane proteolysis. Familial Alzheimer disease (FAD)-linked PSEN mutations alter APP processing in a manner that increases the relative abundance of longer Aβ42 peptides to that of Aβ40 peptides. The mechanisms by which Aβ40 and Aβ42 peptides are produced in a ratio of ten to one by wild type presenilin (PS) and by which Aβ42 is overproduced by FAD-linked PS variants are not completely understood. We generated chimeras of the amyloid precursor protein C-terminal fragment (C99) and PS to address this issue. We found a chimeric protein where C99 is fused to the PS1 N-terminus undergoes in cis processing to produce Aβ and that a fusion protein harboring FAD-linked PS1 mutations overproduced Aβ42. To change the molecular interactions within the C99-PS1 fusion protein, we made sequential deletions of the junction between C99 and PS1. We found differential effects of deletion in C99-PS1 on Aβ40 and 42 production. Deletion of the junction between APP CTF and PS1 in the fusion protein decreased Aβ40, while it did not decrease Aβ42 production in the presence or absence of FAD-linked PS1 mutation. These results are consistent with the idea that the APP/PS interaction is differentially regulated during Aβ40 and 42 production.
Related Links	http://dx.doi.org/10.1371/journal.pone.0048551
Starting Page	48551
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	11
Volume Number	7
Language	English
Publisher	Public Library of Science
Publisher Date	2012-11-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Correction: Differential Regulation of Amyloid Precursor Protein/Presenilin 1 Interaction during Ab40/42 Production Detected Using Fusion Constructs

Generation of Amyloid-β Is Reduced by the Interaction of Calreticulin with Amyloid Precursor Protein, Presenilin and Nicastrin

Peptides of Presenilin-1 Bind the Amyloid Precursor Protein Ectodomain and Offer a Novel and Specific Therapeutic Approach to Reduce ß-Amyloid in Alzheimer’s Disease

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Differential Regulation of Amyloid Precursor Protein/Presenilin 1 Interaction during Ab40/42 Production Detected Using Fusion Constructs

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Correction: Differential Regulation of Amyloid Precursor Protein/Presenilin 1 Interaction during Ab40/42 Production Detected Using Fusion Constructs

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