title: Increased levels of plasma p3-alcα35, a major fragment of Alcadeinα by γ-secretase cleavage, in Alzheimer's disease.
abstract: p3-Alcα is a metabolic fragment of Alcadeinα (Alcα). Similar to the generation of the p3 fragment from amyloid-β protein precursor (AβPP) processing, Alcα is cleaved by α- and γ-secretases, leading to the secretion of p3-Alcα peptides into cerebrospinal fluid (CSF). p3-Alcα is also detected in the plasma, similar to amyloid-β (Aβ), which is a metabolic fragment of AβPP cleaved by amyloidogenic β- and γ-secretases. Because p3-Alcα is a non-aggregatable and stable peptide, unlike aggregatable Aβ and metabolically labile p3 of AβPP, the changes of p3-Alcα in quality and/or quantity in CSF and plasma are expected to be a marker for assessing alteration of substrate cleavage by γ-secretase, such as Aβ generation from AβPP. The present study describes a sandwich enzyme-linked immunosorbent assay for quantifying levels of p3-Alcα35, the major form of the p3-Alcα species, and examines levels of p3-Alcα35 in the plasma of three independent Japanese cohorts. In two of the three cohorts, the p3-Alcα35 levels were significantly increased with a concomitant decrease in the Mini-Mental State Examination score, or in clinically diagnosed Alzheimer's disease (AD) patients, when compared with age-matched non-demented subjects. The values were significantly lower in AD subjects who were administered donepezil, when compared to AD subjects without donepezil treatment. The increase in plasma p3-Alcα35 levels may indicate an endophenotype in subjects in whom AD is due to a progressing cognitive impairment in subjects with a γ-secretase malfunction, or a disorder of the clearance of peptides.
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Chiori
authors.initials: C
authors.lastname: Omori
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Kaneko
authors.affiliation: Department of Neuropsychiatry, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Nakajima
authors.affiliation: Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.affiliation: Department of Neurology, Higashi Matsudo Municipal Hospital, Matsudo, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Waragai
authors.affiliation: Immuno-Biological Laboratories Co., Ltd. (IBL), Fujioka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Department of Molecular Neuropathology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Morishima-Kawashima
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakaya
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Taru
authors.affiliation: Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Miki-cho, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Neuropsychiatry, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Asada
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Hata
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000175:diagnosis* / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000097:blood* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000097:blood* / Q000378:metabolism; D003072:Cognition Disorders / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy; D015331:Cohort Studies; D018450:Disease Progression; D000077265:Donepezil; D058068:Endophenotypes / Q000097:blood; D005260:Female; D006801:Humans; D007189:Indans / Q000627:therapeutic use; D008297:Male; D018697:Nootropic Agents / Q000627:therapeutic use; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000097:blood* / Q000378:metabolism; D010880:Piperidines / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; C503225:CLSTN1 protein, human; D002135:Calcium-Binding Proteins; D007189:Indans; D018697:Nootropic Agents; D010446:Peptide Fragments; D010880:Piperidines; D000077265:Donepezil; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; alcadein; diagnosis; donepezil; p3-Alc; plasma biomarker; γ-secretase