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

• DOI: 10.1021/ja054041c
• Publication Date: 2005-10-26T04:25:28Z
• Authors: Kazuma Murakami; Kazuhiro Irie; Hajime Ohigashi; Hideyuki Hara; Masaya Nagao; Takahiko Shimizu; Takuji Shirasawa
• Keywords: Models, Molecular; 0303 health sciences; Amyloid beta-Peptides; Free Radicals; Electron Spin Resonance Spectroscopy; Models, Biological; Peptide Fragments; 3. Good health; Kinetics; Oxidative Stress; 03 medical and health sciences; Methionine; Alzheimer Disease; Cations; Tyrosine; Sulfhydryl Compounds; Peptides; Oxidation-Reduction

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