PT  - JOURNAL ARTICLE
AU  - Yue Qi-Takahara
AU  - Maho Morishima-Kawashima
AU  - Yu Tanimura
AU  - Georgia Dolios
AU  - Naoko Hirotani
AU  - Yuko Horikoshi
AU  - Fuyuki Kametani
AU  - Masahiro Maeda
AU  - Takaomi C. Saido
AU  - Rong Wang
AU  - Yasuo Ihara
TI  - Longer Forms of Amyloid β Protein: Implications for the Mechanism of Intramembrane Cleavage by γ-Secretase
AID  - 10.1523/JNEUROSCI.1575-04.2005
DP  - 2005 Jan 12
TA  - The Journal of Neuroscience
PG  - 436--445
VI  - 25
IP  - 2
4099  - http://www.jneurosci.org/content/25/2/436.short
4100  - http://www.jneurosci.org/content/25/2/436.full
SO  - J. Neurosci.2005 Jan 12; 25
AB  - 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.