A novel bifunctional non-natural tetrapeptide, Met-Asp-d-Trp-Aib, is capable of binding copper, competing with amyloid-beta peptide (Aβ) for Cu(ii), and modulating Aβ aggregation. The study of this tetrapeptide provides further insights into the role of Cu(ii) in the Aβ aggregation pathway, and into the design of compounds with therapeutic potential for Alzheimer's disease.
Alzheimer's disease is a neurodegenerative condition characterized by an accumulation of toxic amyloid beta- (A-)peptides in the brain causing progressive neuronal death. A-peptides are produced by aspartyl proteinase-mediated cleavage of the larger amyloid precursor protein (APP). In contrast to this detrimental “amyloidogenic” form of proteolysis, a range of zinc metalloproteinases can process APP via an alternative “nonamyloidogenic” pathway in which the protein is cleaved within its A region thereby precluding the formation of intact A-peptides. In addition, other members of the zinc metalloproteinase family can degrade preformed A-peptides. As such, the zinc metalloproteinases, collectively, are key to downregulating A generation and enhancing its degradation. It is the role of zinc metalloproteinases in this “positive side of proteolysis in Alzheimer's disease” that is discussed in the current paper.
Role of a tyrosine residue in metal-induced aggregation of the amyloid beta-peptide