Decrease in p3-Alcβ37 and p3-Alcβ40, products of Alcadein β generated by γ-secretase cleavages, in aged monkeys and patients with Alzheimer's disease

• Published in: Alzheimer's & dementia : translational research & clinical interventions 2019, Vol.5 (1), p.740-750
• Main Authors: Hata, Saori, Omori, Chiori, Kimura, Ayano, Saito, Haruka, Kimura, Nobuyuki, Gupta, Veer, Pedrini, Steve, Hone, Eugene, Chatterjee, Pratishtha, Taddei, Kevin, Kasuga, Kensaku, Ikeuchi, Takeshi, Waragai, Masaaki, Nishimura, Masaki, Hu, Anqi, Nakaya, Tadashi, Meijer, Laurent, Maeda, Masahiro, Yamamoto, Tohru, Masters, Colin L., Rowe, Chris C., Ames, David, Yamamoto, Kazuo, Martins, Ralph N., Gandy, Sam, Suzuki, Toshiharu
• Format: Article
• Language: English
• Subjects: Aftin-5; Alcadein; Alzheimer's disease; Amyloid β-peptide; Calsyntenin; Cerebrospinal fluid; p3-Alc; γ-secretase
• ISSN: 2352-8737; 2352-8737
• DOI: 10.1016/j.trci.2019.09.015

Neuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets. We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). In monkeys, CSF p3-Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3-Alcβ levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcβ level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcβ37 while increasing the production of Aβ42. Aging decreases the generation of p3-Alcβ, and further significant decrease of p3-Alcβ caused by aberrant γ-secretase activity may accelerate pathogenesis in AD.