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The Journal of Neuroscience, January 12, 2005, 25(2):436-445; doi:10.1523/JNEUROSCI.1575-04.2005

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Neurobiology of Disease
Longer Forms of Amyloid Protein: Implications for the Mechanism of Intramembrane Cleavage by -Secretase

Yue Qi-Takahara,¹ Maho Morishima-Kawashima,¹ Yu Tanimura,¹ Georgia Dolios,² Naoko Hirotani,³ Yuko Horikoshi,⁵ Fuyuki Kametani,⁶ Masahiro Maeda,⁵ Takaomi C. Saido,⁴ Rong Wang,² and 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 ⁴Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, Saitama 351-0198, Japan, ⁵Immuno-Biological Laboratories Company, Ltd., Gunma 375-0005, Japan, and ⁶Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo 156-8585, Japan

-Cleavage of -amyloid precursor protein (APP) in the middle of the cell membrane generates amyloid protein (A), and -cleavage, 10 residues downstream of the -cleavage site, releases the APP intracellular domain (AICD). A significant link between generation of A and AICD and failure to detect AICD41-99 led us to hypothesize that -cleavage generates longer As, which are then processed to A40/42. Using newly developed gel systems and an N-end-specific monoclonal antibody, we have identified the longer As (A1-43, A1-45, A1-46, and A1-48) within the cells and in brain tissues. The production of these longer As as well as A40/42 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 -secretase inhibitor, builds up A1-43 and A1-46 intracellularly, which was also confirmed by mass spectrometry. Notably, suppression of A40 appeared to lead to an increase in A43, which in turn brings an increase in A46, in a dose-dependent manner. We therefore propose an -helical model in which longer A species generated by -cleavage is cleaved at every three residues in its carboxyl portion.

Key words: amyloid -protein; APP; -secretase; intramembrane cleavage; presenilin; Alzheimer's disease

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Received April 25, 2004; revised November 26, 2004; accepted November 29, 2004.

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