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

Saori Hata; Chiori Omori; Ayano Kimura; Haruka Saito; Nobuyuki Kimura; Veer Gupta; Steve Pedrini; Eugene Hone; Pratishtha Chatterjee; Kevin Taddei; Kensaku Kasuga; Takeshi Ikeuchi; Masaaki Waragai; Masaki Nishimura; Anqi Hu; Tadashi Nakaya; Laurent Meijer; Masahiro Maeda; Tohru Yamamoto; Colin L. Masters; Chris C. Rowe; David Ames; Kazuo Yamamoto; Ralph N. Martins; Sam Gandy; Toshiharu Suzuki

doi:10.1016/j.trci.2019.09.015

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

Saori Hata^*, Chiori Omori, Ayano Kimura, Haruka Saito, Nobuyuki Kimura, Veer Gupta, Steve Pedrini, Eugene Hone, Pratishtha Chatterjee, Kevin Taddei, Kensaku Kasuga, Takeshi Ikeuchi, Masaaki Waragai, Masaki Nishimura, Anqi Hu, Tadashi Nakaya, Laurent Meijer, Masahiro Maeda, Tohru Yamamoto, Colin L. MastersChris C. Rowe, David Ames, Kazuo Yamamoto, Ralph N. Martins, Sam Gandy, Toshiharu Suzuki

^*Corresponding author for this work

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Abstract

Introduction: 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. Methods: We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). Results: 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. Discussion: 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.

Original language	English
Pages (from-to)	740-750
Number of pages	11
Journal	Alzheimer's and Dementia: Translational Research and Clinical Interventions
Volume	5
Issue number	1
DOIs	https://doi.org/10.1016/j.trci.2019.09.015
Publication status	Published - 1 Jan 2019

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

Aftin-5
Alcadein
Alzheimer's disease
Amyloid β-peptide
Calsyntenin
Cerebrospinal fluid
p3-Alc
γ-secretase

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10.1016/j.trci.2019.09.015

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Hata, S., Omori, C., Kimura, A., Saito, H., Kimura, N., Gupta, V., Pedrini, S., Hone, E., Chatterjee, P., Taddei, K., Kasuga, K., Ikeuchi, T., Waragai, M., Nishimura, M., Hu, A., Nakaya, T., Meijer, L., Maeda, M., Yamamoto, T., ... Suzuki, T. (2019). 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. Alzheimer's and Dementia: Translational Research and Clinical Interventions, 5(1), 740-750. https://doi.org/10.1016/j.trci.2019.09.015

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title = "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",

abstract = "Introduction: 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. Methods: We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). Results: 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. Discussion: 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.",

keywords = "Aftin-5, Alcadein, Alzheimer's disease, Amyloid β-peptide, Calsyntenin, Cerebrospinal fluid, p3-Alc, γ-secretase",

author = "Saori Hata and Chiori Omori and Ayano Kimura and Haruka Saito and Nobuyuki Kimura and Veer Gupta and Steve Pedrini and Eugene Hone and Pratishtha Chatterjee and Kevin Taddei and Kensaku Kasuga and Takeshi Ikeuchi and Masaaki Waragai and Masaki Nishimura and Anqi Hu and Tadashi Nakaya and Laurent Meijer and Masahiro Maeda and Tohru Yamamoto and Masters, \{Colin L.\} and Rowe, \{Chris C.\} and David Ames and Kazuo Yamamoto and Martins, \{Ralph N.\} and Sam Gandy and Toshiharu Suzuki",

note = "Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2019",

month = jan,

day = "1",

doi = "10.1016/j.trci.2019.09.015",

language = "English",

volume = "5",

pages = "740--750",

journal = "Alzheimer's and Dementia: Translational Research and Clinical Interventions",

issn = "2352-8737",

publisher = "John Wiley \& Sons",

number = "1",

}

Hata, S, Omori, C, Kimura, A, Saito, H, Kimura, N, Gupta, V, Pedrini, S, Hone, E, Chatterjee, P, Taddei, K, Kasuga, K, Ikeuchi, T, Waragai, M, Nishimura, M, Hu, A, Nakaya, T, Meijer, L, Maeda, M, Yamamoto, T, Masters, CL, Rowe, CC, Ames, D, Yamamoto, K, Martins, RN, Gandy, S & Suzuki, T 2019, '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', Alzheimer's and Dementia: Translational Research and Clinical Interventions, vol. 5, no. 1, pp. 740-750. https://doi.org/10.1016/j.trci.2019.09.015

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. / Hata, Saori; Omori, Chiori; Kimura, Ayano et al.
In: Alzheimer's and Dementia: Translational Research and Clinical Interventions, Vol. 5, No. 1, 01.01.2019, p. 740-750.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Hata, Saori

AU - Omori, Chiori

AU - Kimura, Ayano

AU - Saito, Haruka

AU - Kimura, Nobuyuki

AU - Gupta, Veer

AU - Pedrini, Steve

AU - Hone, Eugene

AU - Chatterjee, Pratishtha

AU - Taddei, Kevin

AU - Kasuga, Kensaku

AU - Ikeuchi, Takeshi

AU - Waragai, Masaaki

AU - Nishimura, Masaki

AU - Hu, Anqi

AU - Nakaya, Tadashi

AU - Meijer, Laurent

AU - Maeda, Masahiro

AU - Yamamoto, Tohru

AU - Masters, Colin L.

AU - Rowe, Chris C.

AU - Ames, David

AU - Yamamoto, Kazuo

AU - Martins, Ralph N.

AU - Gandy, Sam

AU - Suzuki, Toshiharu

N1 - Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Introduction: 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. Methods: We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). Results: 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. Discussion: 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.

AB - Introduction: 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. Methods: We developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF). Results: 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. Discussion: 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.

KW - Aftin-5

KW - Alcadein

KW - Alzheimer's disease

KW - Amyloid β-peptide

KW - Calsyntenin

KW - Cerebrospinal fluid

KW - p3-Alc

KW - γ-secretase

UR - https://www.scopus.com/pages/publications/85074520391

U2 - 10.1016/j.trci.2019.09.015

DO - 10.1016/j.trci.2019.09.015

M3 - Article

C2 - 31754625

AN - SCOPUS:85074520391

SN - 2352-8737

VL - 5

SP - 740

EP - 750

JO - Alzheimer's and Dementia: Translational Research and Clinical Interventions

JF - Alzheimer's and Dementia: Translational Research and Clinical Interventions

IS - 1

ER -

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

Abstract

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Keywords

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