Alcadein cleavages by amyloid beta-precursor protein (APP) alpha- and gamma-secretases generate small peptides, p3-Alcs, indicating Alzheimer disease-related gamma-secretase dysfunction.
Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc(alpha), Alc(beta), and Alc(gamma). 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 alpha-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 gamma-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma), 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 beta-amyloid species Abeta42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma) were not equivalent, suggesting that one type of gamma-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 gamma-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects.
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Saori
S
Hata
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Sayaka
S
Fujishige
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Yoichi
Y
Araki
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Naoko
N
Kato
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Masahiko
M
Araseki
Neurology Unit, Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu 520-2192, Japan.
Masaki
M
Nishimura
Department of Anatomy, University of Bonn, 53115 Bonn, Germany.
Dieter
D
Hartmann
Institute of Biochemistry, University of Kiel, Kiel, Germany.
Paul
P
Saftig
Institute of Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
Falk
F
Fahrenholz
Department of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
Miyako
M
Taniguchi
Department of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
Katsuya
K
Urakami
Choju Medical Institute, Fukushimura Hospital, Toyohashi 441-8124, Japan.
Hiroyasu
H
Akatsu
Centre of Excellence for Alzheimer's Disease Research and Care and the Sir James McCusker Alzheimer's Disease Research Unit, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, 6027 Western Australia, Australia.
Ralph N
RN
Martins
Department of Integrated Bioscience, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa 277-8562, Japan.
Kazuo
K
Yamamoto
Immuno-Biological Laboratories Co., Ltd., Fujioka 375-0005, Japan.
Masahiro
M
Maeda
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Tohru
T
Yamamoto
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Tadashi
T
Nakaya
Department of Neurology and Psychiatry, Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, New York 10029; James J. Peters Veterans Administration Medical Center, Bronx, New York 10468. Electronic address: samuel.gandy@mssm.edu.
Sam
S
Gandy
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. Electronic address: tsuzuki@pharm.hokudai.ac.jp.
Toshiharu
T
Suzuki
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D010455:Peptides; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse