Formation and stabilization model of the 42-mer Aβ radical:: Implications for the long-lasting oxidative stress in Alzheimer's disease

Amyloid fibrils mainly consist of 40-mer and 42-mer peptides (A beta 40, A beta 42). A beta 42 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 A beta 40. The neurotoxicity of A beta 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 A beta 42 and A beta 40 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 A beta 42 has a C-terminal beta-sheet region. Our biophysical study on A beta 42 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 beta-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 A beta 42. In contrast, the S-oxidized radical cation of A beta 40 is too short-lived to induce potent neurotoxicity because no such stabilization of radicals occurs in A beta 40.