E22Δ Mutation in Amyloid β‐Protein Promotes β‐Sheet Transformation, Radical Production, and Synaptotoxicity, But Not Neurotoxicity

Oligomers of 40‐ or 42‐mer amyloid β ‐protein (A β 40, A β 42) cause cognitive decline and synaptic dysfunction in Alzheimer′s disease. We proposed the importance of a turn at Glu22 and Asp23 of A β 42 to induce its neurotoxicity through the formation of radicals. Recently, a novel deletion mutant at Glu22 (E22Δ) of A β 42 was reported to accelerate oligomerization and synaptotoxicity. To investigate this mechanism, the effects of the E22Δ mutation in A β 42 and A β 40 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‐A β 42 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‐A β is similar to that in E22P‐A β 42 but not the same, since E22Δ‐A β 42 exhibited no cytotoxicity, unlike E22P‐A β 42 and wild‐type A β 42.