Alcadein cleavages by amyloid β-precursor protein (APP) α- and γ-secretases generate small peptides, p3-Alcs, indicating Alzheimer disease-related γ-secretase dysfunction

Saori Hata, Sayaka Fujishige, Yoichi Araki, Naoko Kato, Masahiko Araseki, Masaki Nishimura, Dieter Hartmann, Paul Saftig, Falk Fahrenholz, Miyako Taniguchi, Katsuya Urakami, Hiroyasu Akatsu, Ralph N. Martins, Kazuo Yamamoto, Masahiro Maeda, Tohru Yamamoto, Tadashi Nakaya, Sam Gandy*, Toshiharu Suzuki

*Corresponding author for this work

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 ADAM10 andADAM17 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).Wedetermined 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.

Original languageEnglish
Pages (from-to)36024-36033
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number52
DOIs
Publication statusPublished - 25 Dec 2009
Externally publishedYes

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