Identifying, By First-Principles Simulations, Cu[Amyloid-β] Species Making Fenton-Type Reactions in Alzheimer’s Disease

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• 作者：Giovanni La Penna ; Christelle Hureau ; Oliviero Andreussi ; Peter Faller
• 刊名：Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：December 27, 2013
• 年：2013
• 卷：117
• 期：51
• 页码：16455-16467
• 全文大小：474K
• ISSN：1520-5207

文摘

According to the amyloid cascade hypothesis, amyloid-尾 peptides (A尾) play a causative role in Alzheimer鈥檚 disease (AD), of which oligomeric forms are proposed to be the most neurotoxic by provoking oxidative stress. Copper ions seem to play an important role as they are bound to A尾 in amyloid plaques, a hallmark of AD. Moreover, Cu鈥揂尾 complexes are able to catalyze the production of hydrogen peroxide and hydroxyl radicals, and oligomeric Cu鈥揂尾 was reported to be more reactive. The flexibility of the unstructured A尾 peptide leads to the formation of a multitude of different forms of both Cu(I) and Cu(II) complexes. This raised the question of the structure鈥揻unction relationship. We address this question for the biologically relevant Fenton-type reaction. Computational models for the Cu鈥揂尾 complex in monomeric and dimeric forms were built, and their redox behavior was analyzed together with their reactivity with peroxide. A set of 16 configurations of Cu鈥揂尾 was studied and the configurations were classified into 3 groups: (A) configurations that evolve into a linearly bound and nonreactive Cu(I) coordination; (B) reactive configurations without large reorganization between the two Cu redox states; and (C) reactive configurations with an open structure in the Cu(I)鈥揂尾 coordination, which have high water accessibility to Cu. All the structures that showed high reactivity with H₂O₂ (to form HO^{鈥?/sup>) fall into class C. This means that within all the possible configurations, only some pools are able to produce efficiently the deleterious HO鈥?/sup>, while the other pools are more inert. The characteristics of highly reactive configurations consist of a N鈥揅u(I)鈥揘 coordination with an angle far from 180掳 and high water crowding at the open side. This allows the side-on entrance of H₂O₂ and its cleavage to form a hydroxyl radical. Interestingly, the reactive Cu(I)鈥揂尾 states originated mostly from the dimeric starting models, in agreement with the higher reactivity of oligomers. Our study gives a rationale for the Fenton-type reactivity of Cu鈥揂尾 and how dimeric Cu鈥揂尾 could lead to a higher reactivity. This opens a new therapeutic angle of attack against Cu鈥揂尾-based reactive oxygen species production.}