Longer Forms of Amyloid β Protein: Implications for the Mechanism of Intramembrane Cleavage by γ-Secretase

Journal of Neuroscience - Tập 25 Số 2 - Trang 436-445 - 2005
Yue Qi-Takahara1, Maho Morishima‐Kawashima1, Yu Tanimura1, Georgia Dolios2, Naoko Hirotani3, Yuko Horikoshi4, Fuyuki Kametani5, Masahiro Maeda4, Takaomi C. Saido6, Rong Wang2, Yasuo Ihara1
1Department of Neuropathology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan
2Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029-6574,
3Resources Center and
4Immuno-Biological Laboratories Company, Ltd., Gunma 375-0005, Japan, and
5Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo, 156-8585, Japan
6Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, Saitama 351-0198, Japan,

Tóm tắt

γ-Cleavage of β-amyloid precursor protein (APP) in the middle of the cell membrane generates amyloid β protein (Aβ), and ϵ-cleavage, ∼10 residues downstream of the γ-cleavage site, releases the APP intracellular domain (AICD). A significant link between generation of Aβ and AICD and failure to detect AICD41-99 led us to hypothesize that ϵ-cleavage generates longer Aβs, which are then processed to Aβ40/42. Using newly developed gel systems and an N-end-specific monoclonal antibody, we have identified the longer Aβs (Aβ1-43, Aβ1-45, Aβ1-46, and Aβ1-48) within the cells and in brain tissues. The production of these longer Aβs as well as Aβ40/42 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 γ-secretase inhibitor, builds up Aβ1-43 and Aβ1-46 intracellularly, which was also confirmed by mass spectrometry. Notably, suppression of Aβ40 appeared to lead to an increase in Aβ43, which in turn brings an increase in Aβ46, in a dose-dependent manner. We therefore propose an α-helical model in which longer Aβ species generated by ϵ-cleavage is cleaved at every three residues in its carboxyl portion.

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Thông tin
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Journal of Neuroscience

Tập 25 Số 2

436-445

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