Distance and meausurement between Tyr10 and Met35 in amyloid β by site-directed spin-labeling ESR spectroscopy: Implications for the stronger neurotoxicity of Aβ42 than Aβ40

The neurotoxicity of the 42-mer and 40-mer amyloid β peptides (Aß42 and Aß40) is closely related to the radicalization at both Tyr10 and Met35. Aß42 is more neurotoxic than Aß40. Our previous structural analyses of Aß42 suggested that Tyr10 and Met35 are brought closer together by the turn at positions 22 and 23, and the S-oxidized radical cation at position 35, which is the ultimate toxic radical species, can be produced effectively through oxidation by the phenoxy radical at position 10. To verify this idea, their separation was measured by site-directed spin labeling (MTSSL) by using ESR spectroscopy. Among the three kinds of Aß42 derivatives, which are doubly or singly spin-labeled at position 10 and 35, only 10,35-MTSSL-Aß42 showed a clear dipole coupling in continuous-wave ESR; this suggests that the intramolecular spin labels at position 10 and 35 in Aß42 are located within ∼ 15 -riA. In contrast, 10,35-MTSSL-Aß40 did not give such signals. The distance between Tyr10 and Met35 in 10,35-MTSSLAß40, which was successfully measured by pulsed ESR spectroscopy was 30 Å long. The difference in the distance between Aß42 and Aß40 could explain in part the stronger neurotoxicity of Aß42 compared to Aß40.