title: E22Δ Mutation in Amyloid β-Protein Promotes β-Sheet Transformation, Radical Production, and Synaptotoxicity, But Not Neurotoxicity.
abstract: Oligomers of 40- or 42-mer amyloid β-protein (Aβ40, Aβ42) cause cognitive decline and synaptic dysfunction in Alzheimer's disease. We proposed the importance of a turn at Glu22 and Asp23 of Aβ42 to induce its neurotoxicity through the formation of radicals. Recently, a novel deletion mutant at Glu22 (E22Δ) of Aβ42 was reported to accelerate oligomerization and synaptotoxicity. To investigate this mechanism, the effects of the E22Δ mutation in Aβ42 and Aβ40 on the transformation of β-sheets, radical production, and neurotoxicity were examined. Both mutants promoted β-sheet transformation and the formation of radicals, while their neurotoxicity was negative. In contrast, E22P-Aβ42 with a turn at Glu22 and Asp23 exhibited potent neurotoxicity along with the ability to form radicals and potent synaptotoxicity. These data suggest that conformational change in E22Δ-Aβ is similar to that in E22P-Aβ42 but not the same, since E22Δ-Aβ42 exhibited no cytotoxicity, unlike E22P-Aβ42 and wild-type Aβ42.
authors.affiliation: Laboratory of Organic Chemistry in Life Science, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kazuma
authors.initials: K
authors.lastname: Murakami
authors.forename: Naotaka
authors.initials: N
authors.lastname: Izuo
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
authors.forename: Tetsu
authors.initials: T
authors.lastname: Nagata
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
authors.forename: Takami
authors.initials: T
authors.lastname: Tomiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takuma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie