Increased Levels of Plasma p3-Alcα35, a Major Fragment of Alcadeinα by γ-Secretase Cleavage, in Alzheimer's Disease

Article type: Research Article

Authors: Omori, Chiori^a | Kaneko, Madoka^a | Nakajima, Etsuko^b | Akatsu, Hiroyasu^c | Waragai, Masaaki^d | Maeda, Masahiro^e | Morishima-Kawashima, Maho^f | Saito, Yuhki^a | Nakaya, Tadashi^a | Taru, Hidenori^a | Yamamoto, Tohru^g | Asada, Takashi^b | Hata, Saori^{a; *} | Suzuki, Toshiharu^{a; *} | for the Japanese Alzheimer's Disease Neuroimaging Initiative

Affiliations: [a] Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan | [b] Department of Neuropsychiatry, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan | [c] Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan | [d] Department of Neurology, Higashi Matsudo Municipal Hospital, Matsudo, Japan | [e] Immuno-Biological Laboratories Co., Ltd. (IBL), Fujioka, Japan | [f] Department of Molecular Neuropathology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan | [g] Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Miki-cho, Japan

Correspondence: [*] Correspondence to: Saori Hata and Toshiharu Suzuki, Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita12-Nishi6, Kita-ku, Sapporo 060-0812, Japan. Tel.: +81 11 706 3250; Fax: +81 11 706 4991; E-mails: [email protected]; [email protected].

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.

Keywords: Alzheimer's disease, alcadein, diagnosis, donepezil, γ-secretase, p3-Alc, plasma biomarker

DOI: 10.3233/JAD-131610

Journal: Journal of Alzheimer's Disease, vol. 39, no. 4, pp. 861-870, 2014