34 GHz Pulsed ENDOR Characterization of the Copper Coordination of an Amyloid β Peptide Relevant to Alzheimer's Disease

摘要

Alzheimer's disease (AD), a neurodegenerative disorder, afflicts more than 26 million people worldwide. However, no drugs or therapeutics have been developed to date to treat AD. The presence of accumulated amyloid plaques is the pathological hallmark of AD, and high concentrations of copper ions are found within the plaques. Furthermore, there is growing evidence that copper ions play an important role in AD pathogenesis by an oxidative stress pathway. The coordination of copper(II) to amyloid-P peptide (A(3) has been shown to affect the key feature of the peptide structure, and thus, the structure controls the catalytic production of reactive oxygen species. Because the coordination environment has a critical effect on copper reactivity, the elucidation of the structural details of the Cu~(II) coordination sphere is essential in understanding the molecular mechanisms of amyloid fibrillization. Moreover, in-depth knowledge of the coordination environment of Cu~(II) in amyloid peptide at the molecular level is particularly important for the rational design of therapeutic agents for AD. Thus, exploration of the coordination environment of Cu~(II) has been a main theme in this research area. However, the unambiguous identification of the Cu~(II) coordination mode still remains to be achieved.