P-55 βアミロイドの新しい凝集モデルに基づく神経細胞毒性発現機構(ポスター発表の部)

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Amyloid fibrils mainly consist of 42-mer and 40-mer peptides (Aβ42, Aβ40). Aβ42 plays a pivotal role in the pathogenesis of Alzheimer's disease since its aggregative ability and neurotoxicity are considerably greater than those of Aβ40. The systematic proline replacement of Aβ42 led us to propose a new aggregation model of Aβ42, where the turn structure at positions 22 and 23 along with the intermolecular β-sheets at positions 15-21 and 24-32, and the intramolecular β-sheets at the C-terminus (at positions 35-37 and 40-42) are indispensable for the aggregation (Fig. 3). The neurotoxicity of Aβ peptides involving the generation of free radicals is closely related to the S-oxidized radical cation of Met-35. However, its origin and mechanism of stabilization remain unclear. Our biophysical study on several Aβ42 mutants using ESR spectrometry suggested that the S-oxidized radical cation of Met-35 could be generated by the reduction of the tyrosyl radical at Tyr-10 through the turn structure at positions 22 and 23, and stabilized by a C-terminal carboxylate anion through the intramolecular β-sheets at the C-terminus to form a C-terminal core that would lead to aggregation (Fig. 6). In contrast, the S-oxidized radical cation of Aβ40 is deduced to be too short-lived to induce neurotoxicity since such a radical stabilization does not occur in Aβ40. This explains well the large difference in the aggregative ability and neurotoxicity between Aβ42 and Aβ40. Our new model gives unique opportunities to design inhibitors and antibodies that are specific to the 'malignant' conformation of Aβ42 (Fig. 6).
天然有機化合物討論会の論文
2005-09-15

P-55 βアミロイドの新しい凝集モデルに基づく神経細胞毒性発現機構(ポスター発表の部)

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