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The Journal of Neuroscience, October 14, 2009, 29(41):13042-13052; doi:10.1523/JNEUROSCI.2362-09.2009

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Neurobiology of Disease
-Secretase: Successive Tripeptide and Tetrapeptide Release from the Transmembrane Domain of β-Carboxyl Terminal Fragment

Mako Takami,¹ Yu Nagashima,² Yoshihisa Sano,³ Seiko Ishihara,¹ Maho Morishima-Kawashima,⁴ Satoru Funamoto,¹ and Yasuo Ihara¹

¹Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kizugawa 619-0225, Japan, ²Department of Neurology, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan, ³Drug Metabolism and Pharmacokinetics Research Section, Eisai Company Ltd., Tsukuba 300-2635, Japan, and ⁴Department of Molecular Neuropathology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

Correspondence should be addressed to Dr. Yasuo Ihara, Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, 4-1-1, Kizugawadai, Kizugawa 619-0225, Japan. Email: yihara{at}mail.doshisha.ac.jp

Amyloid β protein (Aβ), a pathogenic molecule associated with Alzheimer's disease, is produced by -secretase, which cleaves the β-carboxyl terminal fragment (βCTF) of β-amyloid precursor protein in the middle of its transmembrane domain. How the cleavage proceeds within the membrane has long been enigmatic. We hypothesized previously that βCTF is cleaved first at the membrane–cytoplasm boundary, producing two long Aβs, Aβ₄₈ and Aβ₄₉, which are processed further by releasing three residues at each step to produce Aβ₄₂ and Aβ₄₀, respectively. To test this hypothesis, we used liquid chromatography tandem mass spectrometry (LC-MS/MS) to quantify the specific tripeptides that are postulated to be released. Using CHAPSO (3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxyl-1-propanesulfonate)-reconstituted -secretase system, we confirmed that Aβ₄₉ is converted to Aβ_43/40 by successively releasing two or three tripeptides and that Aβ₄₈ is converted to Aβ_42/38 by successively releasing two tripeptides or these plus an additional tetrapeptide. Most unexpectedly, LC-MS/MS quantification revealed an induction period, 3–4 min, in the generation of peptides. When extrapolated, each time line for each tripeptide appears to intercept the same point on the x-axis. According to numerical simulation based on the successive reaction kinetics, the induction period exists. These results strongly suggest that Aβ is generated through the stepwise processing of βCTF by -secretase.

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Received May 19, 2009; revised Aug. 12, 2009; accepted Sept. 1, 2009.

Correspondence should be addressed to Dr. Yasuo Ihara, Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, 4-1-1, Kizugawadai, Kizugawa 619-0225, Japan. Email: yihara{at}mail.doshisha.ac.jp

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