Generation of soluble oligomeric β-amyloid species via copper catalyzed oxidation with implications for Alzheimer’s disease: A DFT study

Abstract

A mechanism for the oxidation of a dimeric β-amyloid copper ion complex is proposed based on DFT calculations. It involves the Met35 residue, which is believed to be important in the neurotoxicity causing Alzheimer's disease. Oxidation of Met35 is found to proceed readily with dioxygen when two Met35 residues are close to each other and the copper ion. This indicates that oxidants, such as hydrogen peroxide, are not necessary for oxidation of β-amyloid copper ion complexes. Understanding these processes could be pivotal in gaining more knowledge of this complex disease and for the development of therapeutic treatments.Response to Reviewers: We are happy with the favorable comments by the reviewer. A short summary has been added to the manuscript as suggested by the reviewer. AbstractA mechanism for the oxidation of a dimeric -amyloid copper ion complex is proposed based on DFT calculations. It involves the Met35 residue, which is believed to be important in the neurotoxicity causing Alzheimer's disease. Oxidation of Met35 is found to proceed readily with dioxygen when two Met35 residues are close to each other and the copper ion. This indicates that oxidants, such as hydrogen peroxide, are not necessary for oxidation of -amyloid copper ion complexes. Understanding these processes could be pivotal in gaining more knowledge of this complex disease and for the development of therapeutic treatments.

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

“…The metal-binding region of Ab around residues 6-14 has not yet been adequately addressed by MD studies (see below), and there are conflicting results on models obtained for the loop and b-strands associated with the residue 16 -35 region (Chebaro et al 2009;Miller et al 2009;Murray et al 2009a;Hamley et al 2010;Wei et al 2010). The oxidation state of Met35 has long been of interest (Haeffner et al 2010); this residue in the hydrophobic carboxyl terminus may play a role in oligomerization driven by hydrophobic interactions ). Although it has long been suspected that the highly hydrophobic carboxyl terminus of Ab42 is a principal determinant of aggregation, its biophysical role in oligomerization has only recently begun to be addressed using synthetic peptides (Murray et al 2009a;Li et al 2010).…”

“…Depending on the stoichiometry, Cu 2þ -Ab interactions can cause synthetic Ab to aggregate in vitro principally via an oligomer-forming pathway or a fibrillogenic pathway (Brzyska et al 2009;Moore et al 2009;Olofsson et al 2009a;Tõugu et al 2009;Haeffner et al 2010). That is, at subequimolar Cu 2þ :Ab ratios, amyloid fibrils form; at supra-equimolar ratios, stable oligomers form first, then dityrosine cross-linkages occur (Smith et al 2007).…”

Guanidine hydrochloride denaturation of dopamine-induced α-synuclein oligomers: A small-angle X-ray scattering study

“…Conversely, if the complexes were toxic, their activity could be enhanced by their greater stability. Such an enhancement in toxicity conferred by covalent cross‐linking by nonpeptide bonding has been claimed for the amyloid β peptide of Alzheimer's disease . However, membrane association and lipid binding is also important for the functioning of α‐syn.…”

Estudo Teórico De Potenciais Agentes Para O Tratamento Da Doença De Alzheimer Derivados Da 8-Hidroxiquinolina Com Substituintes Do Tipo N-Acil-Hidrazona

“…[14][15][16][17] Aos íons Fe 3+ e Cu 2+ , por serem redox ativos, também é atribuído o fato de serem responsáveis por produzir espécies reativas de oxigênio no cérebro, causando estresse oxidativo (EROs), agravando os danos cerebrais. 16,18,19 O zinco é encontrado no cérebro em concentrações em torno de 150 µmol.L -1 , sendo de vital importância para o bom funcionamento das funções neurológicas. 16 Ao contrário do ferro e do cobre, o zinco não é redox ativo (devido a sua configuração d 10 ), não contribuindo assim para os danos oxidativos observados na DA.…”

“…39 As estruturas otimizadas dos ligantes e complexos foram obtidas através da teoria do funcional de densidade (DFT) com o funcional de troca e correlação híbrido B3LYP (Becke, três parâmetros, Lee-Yang-Parr), que é um dos funcionais mais utilizados no campo dos metais de transição. 19,22,32,40,41 Os cálculos realizados nesse trabalho também forneceram as frequências vibracionais (Tabela 2) e o espectro teórico de infravermelho (IV) do ligante INHHQ (Figura 1S), que apresentaram boa concordância com os resultados experimentais obtidos por Freitas et al 28 Os diagramas de contorno do orbital de fronteira HOMO para os três ligantes são apresentados na Figura 6, enquanto que os percentuais de participação dos possíveis átomos coordenantes, presentes na estrutura dos três ligantes, são apresentados na Tabela 3. Já os 1 Visualmente, o espectro experimental é mais similar ao espectro teórico do isômero 2, devido a um conjunto de bandas presente na região 3000-4000 cm -1 que são observados em ambos os espectros, enquanto que uma banda bem pronunciada na região 3000-3500 cm -1 , presente no espectro do isômero 1, não é encontrada no espectro experimental.…”