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.

2019-11-07

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, Christopher C

Ames, David

Yamamoto, Kazuo

Martins, Ralph N

Gandy, Sam

Suzuki, Toshiharu

Aftin-5

Alcadein

Alzheimer's disease

Amyloid β-peptide

Calsyntenin

Cerebrospinal fluid

p3-Alc

γ-secretase

Journal Article

0000-0003-3910-2453

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.

link

Alzheimer's & dementia (New York, N. Y.) 2019; 5: 740-750

Alzheimer's & dementia (New York, N. Y.)