Alcadein Cleavages by Amyloid Beta-Precursor Protein (APP) a-and y-Secretases Generate Small Peptides, p3-Alcs, Indicating Alzhiemer Disease-related y-Secretase Dysfunction
Authors
Saori Hata, Hokkaido University, Sapporo, Japan
Sayaka Fujishige, Hokkaido University, Sapporo, Japan
Yoichi Araki, Hokkaido University, Sapporo, Japan
Naoko Kato, Hokkaido University, Sapporo, Japan
Masahiko Araseki, Hokkaido University, Sapporo, Japan
Masaki Nishimura, Shiga University of Medical Science, Otsu, Japan
Dieter Hartmann, University of Bonn
Paul Saftig, University of Kiel
Falk Fahrenholz, Johannes Gutenberg-University, Mainz, Germany
Miyako Taniguchi, Tottori University, Yonago, Japan
Katsuya Urakami, Tottori University, Yonago, Japan
Hiroyasu Akatsu, Fukushimura Hospital, Toyohashi, Japan
Ralph Martins, Edith Cowan University
Kazuo Yamamoto, University of Tokyo
Masahiro Maeda, jImmuno-Biological Laboratories Co., Ltd., Fujioka, Japan
Tohru Yamamoto, Hokkaido University, Sapporo, Japan
Tadashi Nakaya, Hokkaido University, Sapporo, Japan
Sam Gandy, Alzheimer’s Disease Research Center, Mount Sinai School of Medicine,New York
Toshiharu Suzuki, Hokkaido University, Sapporo, Japan
Document Type
Journal Article
Publisher
American Society for Biochemistry and Molecular Biology
Faculty
Faculty of Computing, Health and Science
School
School of Exercise, Biomedical and Health Science / Centre of Excellence in Alzheimer’s Disease Research
RAS ID
9046
Abstract
Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alcα, Alcβ, and Alcγ. The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP α-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent γ-secretase complex, thereby generating “APP p3-like” and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alcα, p3-Alcβ, and p3-Alcγ, whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor β-amyloid species Aβ42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alcα, p3-Alcβ, and p3-Alcγ were not equivalent, suggesting that one type of γ-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect γ-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects.
DOI
10.1074/jbc.M109.057497
Access Rights
free_to_read
Comments
Hata, S., Fujishige, S., Araki, Y., Kato, N., Araseki, M., Nishimura, M., Hartmann, D., Saftig, P., Fahrenholz, F., Taniguchi, M., Urakami, K., Akatsu, H., Martins, R. N., Yamamoto, K., Maeda, M., Yamamoto, T., Nakaya, T., Gandy, S., & Suzuki, T. (2009). Alcadein Cleavages by Amyloid Beta-Precursor Protein (APP) a-and y-Secretases Generate Small Peptides, p3-Alcs, Indicating Alzhiemer Disease-related y-Secretase Dysfunction. The Journal of Biological Chemistry, 284(52), 36024-36033. Available here