Formation and Stabilization Model of the 42-mer Aβ Radical: Implications for the Long-Lasting Oxidative Stress in Alzheimer's Disease

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Abstract
Amyloid fibrils mainly consist of 40-mer and 42-mer peptides (Aβ40, Aβ42). Aβ42 is believed to play a crucial role in the pathogenesis of Alzheimer's disease because its aggregative ability and neurotoxicity are considerably greater than those of Aβ40. The neurotoxicity of Aβ peptides involving the generation of free radicals is closely related to the S-oxidized radical cation of Met-35. However, the cation's origin and mechanism of stabilization remain unclear. Recently, structural models of fibrillar Aβ42 and Aβ40 based on systematic proline replacement have been proposed by our group [Morimoto, A.; et al. J. Biol. Chem. 2004, 279, 52781] and Wetzel's group [Williams, A. D.; et al. J. Mol. Biol. 2004, 335, 833], respectively. A major difference between these models is that our model of Aβ42 has a C-terminal β-sheet region. Our biophysical study on Aβ42 using electron spin resonance (ESR) suggests that the S-oxidized radical cation of Met-35 could be generated by the reduction of the tyrosyl radical at Tyr-10 through a turn structure at positions 22 and 23, and stabilized by a C-terminal carboxylate anion through an intramolecular β-sheet at positions 35−37 and 40−42 to form a C-terminal core that would lead to aggregation. A time-course analysis of the generation of radicals using ESR suggests that stabilization of the radicals by aggregation might be a main reason for the long-lasting oxidative stress of Aβ42. In contrast, the S-oxidized radical cation of Aβ40 is too short-lived to induce potent neurotoxicity because no such stabilization of radicals occurs in Aβ40.

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