Thimet Oligopeptidase Cleaves the Full-Length Alzheimer Amyloid Precursor Protein at a .BETA.-Secretase Cleavage Site in COS Cells.

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概要

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• We developed an assay method using a novel quenched fluorescent substrate (QFS) flanking the β-cleavage site of amyloid precursor protein (APP), and purified a candidate β-secre-tase from bovine brain. N-terminal amino acid analysis showed the candidate to be thimet oligopeptidase (TOP). The cDNA for human TOP was cloned from a human brain cDNA library and expressed in COS cells. The enzyme was further purified on a Ni2+-agarose column. TOP cleaved the Swedish Alzheimer's substrate (SEVNLDAEFR) as well as the normal substrate (SEVKMDAEFR). We then coexpressed TOP with APP 695 in COS cells, collected transfected cells and conditioned media, and analyzed them by immunoblotting. The antibody against the specific secreted APP cleaved by β-secretase (sAPPβ) detected the secretion of sAPPβ only from APP/hTOP-overexpressing cells, and not from cells overex-pressing of antisense hTOP cDNA. Finally, we analyzed the immunolocalization of overex-pressed hTOP in COS cells. Most hTOP was localized in the nuclei, but a small amount was localized in the Golgi or other organelles around the nuclei. These results suggest that TOP has a β-secretase-like activity responsible for the processing of APP.

• 社団法人 日本生化学会の論文

著者

• KOIKE Hisashi

  Department of Biochemistry, Meiji Pharmaceutical University

• Ishiura Shoichi

  Department Of Life And Cognitive Sciences College Of Arts And Sciences The University Of Tokyo

• Saido Takaomi

  Laboratory For Proteolytic Neuroscience Riken Brain Science Institute

• Maruyama Kei

  Department Of Molecular Biology Tokyo Institute Of Psychiatry : Department Of Molecular Biology Toky

• SORIMACHI Hiroyuki

  Institute of Molecular and Cellular Biosciences, The University of Tokyo

• SUZUKI Koichi

  Institute of Molecular and Cellular Biosciences, The University of Tokyo

• SEKI Hiroaki

  Institute of Molecular and Cellular Biosciences, The University of Tokyo

• Kinouchi Tadatoshi

  Institute Of Molecular And Cellular Biosciences The University Of Tokyo

• Ito Masayuki

  Institute Of Molecular And Cellular Biosciences The University Of Tokyo

• TOMIOKA Shigeo

  Institute of Applied Microbiology, University of Tokyo

• Kouchi Zen

  Department of Life Science, Graduate School of Arts and Science, The University of Tokyho

• Ishiura Shoichi

  Department of Biochemistry , Graduate School of Pharmaceutical Sciences. Hokkaido University

• Ishiura Shoichi

  Department of Life Science, Graduate School of Arts and Science, The University of Tokyho

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