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.
Hata
Saori
S
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Fujishige
Sayaka
S
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Araki
Yoichi
Y
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Kato
Naoko
N
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Araseki
Masahiko
M
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Nishimura
Masaki
M
Neurology Unit, Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu 520-2192, Japan.
Hartmann
Dieter
D
Department of Anatomy, University of Bonn, 53115 Bonn, Germany.
Saftig
Paul
P
Institute of Biochemistry, University of Kiel, Kiel, Germany.
Fahrenholz
Falk
F
Institute of Biochemistry, Johannes Gutenberg-University, Mainz, Germany.
Taniguchi
Miyako
M
Department of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
Urakami
Katsuya
K
Department of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
Akatsu
Hiroyasu
H
Choju Medical Institute, Fukushimura Hospital, Toyohashi 441-8124, Japan.
Martins
Ralph N
RN
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.
Yamamoto
Kazuo
K
Department of Integrated Bioscience, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa 277-8562, Japan.
Maeda
Masahiro
M
Immuno-Biological Laboratories Co., Ltd., Fujioka 375-0005, Japan.
Yamamoto
Tohru
T
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Nakaya
Tadashi
T
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Gandy
Sam
S
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.
Suzuki
Toshiharu
T
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. Electronic address: tsuzuki@pharm.hokudai.ac.jp.
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