Differential regulation of amyloid precursor protein/presenilin 1 interaction during Aβ40/42 [corrected] production detected using fusion constructs.
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 (...
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2012
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oai:doaj.org-article:8c411ed52888490bb27d7851410612d82021-11-18T08:09:10ZDifferential regulation of amyloid precursor protein/presenilin 1 interaction during Aβ40/42 [corrected] production detected using fusion constructs.1932-620310.1371/journal.pone.0048551https://doaj.org/article/8c411ed52888490bb27d7851410612d82012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23152781/?tool=EBIhttps://doaj.org/toc/1932-6203Beta 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.Naoyuki SatoMasayasu OkochiMitsuru ShinoharaGopal ThinakaranShuko TakedaAkio FukumoriMotoko Shinohara-NomaMari Mori-UedaHizuki HamadaMasatoshi TakedaHiromi RakugiRyuichi MorishitaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e48551 (2012) |
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Medicine R Science Q Naoyuki Sato Masayasu Okochi Mitsuru Shinohara Gopal Thinakaran Shuko Takeda Akio Fukumori Motoko Shinohara-Noma Mari Mori-Ueda Hizuki Hamada Masatoshi Takeda Hiromi Rakugi Ryuichi Morishita Differential regulation of amyloid precursor protein/presenilin 1 interaction during Aβ40/42 [corrected] production detected using fusion constructs. |
| description |
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. |
| format |
article |
| author |
Naoyuki Sato Masayasu Okochi Mitsuru Shinohara Gopal Thinakaran Shuko Takeda Akio Fukumori Motoko Shinohara-Noma Mari Mori-Ueda Hizuki Hamada Masatoshi Takeda Hiromi Rakugi Ryuichi Morishita |
| author_facet |
Naoyuki Sato Masayasu Okochi Mitsuru Shinohara Gopal Thinakaran Shuko Takeda Akio Fukumori Motoko Shinohara-Noma Mari Mori-Ueda Hizuki Hamada Masatoshi Takeda Hiromi Rakugi Ryuichi Morishita |
| author_sort |
Naoyuki Sato |
| title |
Differential regulation of amyloid precursor protein/presenilin 1 interaction during Aβ40/42 [corrected] production detected using fusion constructs. |
| title_short |
Differential regulation of amyloid precursor protein/presenilin 1 interaction during Aβ40/42 [corrected] production detected using fusion constructs. |
| title_full |
Differential regulation of amyloid precursor protein/presenilin 1 interaction during Aβ40/42 [corrected] production detected using fusion constructs. |
| title_fullStr |
Differential regulation of amyloid precursor protein/presenilin 1 interaction during Aβ40/42 [corrected] production detected using fusion constructs. |
| title_full_unstemmed |
Differential regulation of amyloid precursor protein/presenilin 1 interaction during Aβ40/42 [corrected] production detected using fusion constructs. |
| title_sort |
differential regulation of amyloid precursor protein/presenilin 1 interaction during aβ40/42 [corrected] production detected using fusion constructs. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/8c411ed52888490bb27d7851410612d8 |
| work_keys_str_mv |
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