Title

Alcadein Cleavages by Amyloid Beta-Precursor Protein (APP) a-and y-Secretases Generate Small Peptides, p3-Alcs, Indicating Alzhiemer Disease-related y-Secretase Dysfunction

Document Type

Journal Article

Publisher

American Society for Biochemistry and Molecular Biology

Faculty

Computing, Health and Science

School

Exercise, Biomedical and Health Science, Centre for Alzheimer's Disease

RAS ID

9046

Comments

This article was originally published as: Hata, S., Fujishige, S., Araki, Y., Kato, N., Araseki, M., Nishimura, M., Hartmann, D., Saftig, P., Fahrenholz, F., Taniguchi, M., Urakami, K., Akatsu, H., Martins, R. N., Yamamoto, K., Maeda, M., Yamamoto, T., Nakaya, T., Gandy, S., & Suzuki, T. (2009). Alcadein Cleavages by Amyloid Beta-Precursor Protein (APP) a-and y-Secretases Generate Small Peptides, p3-Alcs, Indicating Alzhiemer Disease-related y-Secretase Dysfunction. The Journal of Biological Chemistry, 284(52), 36024-36033. Original article available here

Abstract

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alcα, Alcβ, and Alcγ. The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP α-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent γ-secretase complex, thereby generating “APP p3-like” and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alcα, p3-Alcβ, and p3-Alcγ, whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor β-amyloid species Aβ42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alcα, p3-Alcβ, and p3-Alcγ were not equivalent, suggesting that one type of γ-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect γ-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects.

DOI

10.1074/jbc.M109.057497

 

Link to publisher version (DOI)

10.1074/jbc.M109.057497