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Longer Forms of Amyloid Beta Protein: Implications for the Mechanism of Intramembrane Cleavage by Gamma-Secretase

Longer Forms of Amyloid Beta Protein: Implications for the Mechanism of Intramembrane Cleavage by Gamma-Secretase

Yue Qi-Takahara, Maho Morishima-Kawashima, Yu Tanimura, Georgia Dolios, Naoko Hirotani, Yuko Horikoshi, Fuyuki Kametani, Masahiro Maeda, Takaomi C Saido, Rong Wang, Yasuo Ihara

J Neurosci. 2005 Jan 12;25(2):436-45.

PMID: 15647487

Abstract:

Gamma-cleavage of beta-amyloid precursor protein (APP) in the middle of the cell membrane generates amyloid beta protein (Abeta), and epsilon-cleavage, approximately 10 residues downstream of the gamma-cleavage site, releases the APP intracellular domain (AICD). A significant link between generation of Abeta and AICD and failure to detect AICD41-99 led us to hypothesize that epsilon-cleavage generates longer Abetas, which are then processed to Abeta40/42. Using newly developed gel systems and an N-end-specific monoclonal antibody, we have identified the longer Abetas (Abeta1-43, Abeta1-45, Abeta1-46, and Abeta1-48) within the cells and in brain tissues. The production of these longer Abetas as well as Abeta40/42 is presenilin dependent and is suppressed by {1S-benzyl-4R-[1S-carbamoyl-2-phenylethylcarbamoyl-1S-3-methylbutylcarbamoyl]-2R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester, a transition state analog inhibitor for aspartyl protease. In contrast, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, a potent dipeptide gamma-secretase inhibitor, builds up Abeta1-43 and Abeta1-46 intracellularly, which was also confirmed by mass spectrometry. Notably, suppression of Abeta40 appeared to lead to an increase in Abeta43, which in turn brings an increase in Abeta46, in a dose-dependent manner. We therefore propose an alpha-helical model in which longer Abeta species generated by epsilon-cleavage is cleaved at every three residues in its carboxyl portion.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP470463413	(5-Trimethylsilanylethynyl-pyridin-2-yl)-carbamic acid tert-butyl ester		470463-41-3	Price

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