METALZCOMP

Understanding the role of transition metals in Alzheimer's disease on a molecular level

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 Obiettivo del progetto (Objective)

'The aggregation of the amyloid-beta peptide (A-beta) into fibrils and successively in plaques is the main event in Alzheimer's disease. The A-beta originates from a membrane protein called amyloid-precursor protein. In healthy brain A-beta is present as soluble form and the predominant chains are formed by 40 or 42 amino acids. The oligomers of A-beta, rather then fully formed fibrils, are suspected to have nerotoxic properties. The transition metal zinc, copper, iron are present in amyloid plaques in abnormally elevated concentrations. It has been experimentally observed that Zn(II) and Cu(II) ions bind at A-beta(1-16) N-terminal sequence and influence aggregation behaviour: in particular Zn triggers and accelerates aggregation and Cu slows down or accelerates aggregation, dependently on conditions. Moreover A-beta bonded to Cu or Fe is able, probably by reducing oxygen, to produce reactive-oxygen species that are widely accepted to play a key role in most of neurodegenerative diseases. Afterwards there are several open questions about the metals/A-beta interaction: coordination chemistry, reactivity of these complexes, different behaviour of metals, peptide structure prone to aggregation, mechanisms of metal-induced aggregation. We propose to use computer simulations (both semiempirical and first principles) to understand the metal/A-beta system. Quantum mechanics methods (DFT) will be used to investigate the nature of metal bond and reactivity but statistical mechanics methods will be also necessary to obtain accessible peptide conformations in water. The Car-Parrinello method, that was successfully applied to similar systems in applicant's previous work, will be used. The project includes the acquisition of new relevant experiments on the kinetics of ROS production catalysed by Cu and Fe complexes of Abeta. Experiments will be based on the expertise of the host institution and specific training of the applicant is planned.'

Introduzione (Teaser)

An EU-funded project successfully started piecing together the picture that will uncover the complex molecular mechanics underlying Alzheimer's disease.

Descrizione progetto (Article)

The anatomy of a 'normal' brain is very different to that of a patient with Alzheimer's disease. Overall, the volume of the cerebral cortex, responsible for all intellectual functioning, is reduced and the spaces between the folds in the cortex increase. At microscopic level, the two main changes are seen as so-called plaques and tangles.

Amyloid plaques are mostly made of aggregated B-amyloid peptides (Abs). Plaque formation can lead to neuron dysfunction and death. It is well established that transition metals zinc (Zn), copper (Cu) and iron (Fe) are present in amyloid plaques in abnormally elevated concentrations. They also play an important, although largely unknown, role in the aggregation process.

The 'Understanding the role of transition metals in Alzheimer's disease on a molecular level' (Metalzcomp) project set out to discover how transition metals affect the behaviour of this malfunctioning protein. The researchers produced computer simulations of the behaviour of two simplified amino acids, aspartic acid (Asp1) and alanine (Ala2), to determine their behaviour under two conditions, in a vacuum and in a solvent (water). Results showed that for the interaction of a transition metal and a peptide, the use of a solvent is imperative.

Using computer simulations and a density functional means of analysis, the molecular dynamics of this metal-Ab interaction was investigated. In particular, the team looked at the behaviour of Cu(I) and Cu(II) ions with regard to the amino acid histidine (His).

By comparison of the truncated established model with a completely solvated set-up, a fresh set of molecular mechanics was revealed. The project researchers were able to successfully track the precise molecular movement and displacement of the His in position 6 with relation to water molecules and the role of Cu(I)/Cu(II) ions.

Project results have the potential to provide a basis for further study of behaviour on a sub-microscopic basis of the many complex factors involved in the development of Alzheimer's disease. Unravelling the details at this level will no doubt provide a framework for the development of molecular pharma therapies to target the specific biochemical pathways involved.