The main hypothesis of the past decade states that the first trigger to the events that eventually lead to neuron death, is the deposition of the amyloid-beta peptide into amyloid (that are characteristic of the disease, and contain high levels of common biometals – copper, zinc and iron). So far, it had been proposed that the disturbances in the homoeostasis of Zn(II) and Cu(II) ions cause the deposition of amyloid-beta into plaques, and that the copper and iron hidden in them in turn become responsible for the death of neurons.
In her doctoral thesis Interactions of Alzheimer’s amyloid-β peptides with Zn(II) and Cu(II) ions, done at the Department of Gene Technology in Tallinn University of Technology, Ann Tiiman, now a post-doctoral research fellow at Stockholm University, investigated the corresponding processes in vitro. In the thesis supervised by Senior Research Fellow Vello Tõugu and Professor Peep Palumaa, the binding affinities of the amyloid-beta peptide to Cu(II) and Zn(II) ions were reliably determined and it was established how Zn(II) and Cu(II) ions affect peptide fibrillization.
The fibrillization of the peptide is an auto-catalytic process – it starts up very slowly in the absence of primary fibrillar particles but proceeds with considerable speed in the case of pre-existing fibrils. Since the level of amyloid-beta peptide in the brain is very low, the fibrillization centres are virtually absent because the probability of their formation via peptide oligomerization is extremely low. However, if the balance of the metal ions is disturbed in some parts of the brain, they can bind to amyloid-beta peptide molecules and induce their aggregation. These aggregates can in turn develop into fibrils that initiate the formation of amyloid plaques. The aggregates that contain copper are very toxic in the presence of reducing agents, because they lead to the production of reactive oxygen species. And this, in turn, can be the main mechanism causing the death of neurons in a brain with Alzheimer’s disease.
The proposed mechanism that is based on the experiments in vitro now needs validating in more complex experimental systems.
Copywriter: Marion Jõepera