Advancing knowledge of the pathway to Alzheimer's
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.
