Quantifying the amount and structure of beta-amyloid that is the most harmful to neurons.
The peptide, a small protein, beta-amyloid is strongly associated with Alzheimer’s disease; however, researchers are still looking for unequivocal proof that this peptide is the causal agent of the onset and development of the disease. The main obstacle impeding such confirmation is that beta-amyloid is not harmful when found in isolation but only when it aggregates, that is when it self-assembles to form the so-called amyloid fibrils.
Researchers are not dealing with a single target, beta-amyloid alone, but with multiple ones because each aggregate of peptide, which can go from two units to 3,000 is a potential target. Determining the aggregate responsible for neuronal death is extremely complex and is one of the key issues for confirming or rejecting the hypothesis regarding beta-amyloid.
In their latest work, researchers from IRB Barcelona in collaboration with the University of Barcelona describe a technique that has allowed them, for the first time, to distinguish different types of beta-amyloid aggregates formed during aggregation and in parallel to establish which is most toxic. The study provides further evidence in support of the hypothesis that neuronal death is caused by intermediate aggregates of beta-amyloid and reveals that the development of structure within these aggregates determines their ability to cause neuronal death. The study is published in the journal ACS Chemical Biology.
The study shows that the most toxic aggregates are those formed by 20 to 100 units of beta-amyloid, known as intermediate aggregates or precursor aggregates of beta-amyloid fibrils. In contrast, the smaller aggregates of beta-amyloid and the amyloid fibrils, which can contain up to 3,000 units of the peptide, do not cause neuronal death.
The team prepared neuronal cultures from the mouse hippocampus, the brain region in which neuronal lost is first observed in Alzheimer’s disease. The scientists treated cultures of mouse neurons with samples obtained at different times of the aggregation process. The point at which they observed the highest neuronal death, reaching about 60%, occurred when cells were exposed to intermediate aggregates of beta-amyloid that had developed a certain degree of structure.
The technique set up allowed the researchers to detect how the structure within these aggregates increases, that is to say, how the aggregates take shape and how they get organized. The team observed that maximum toxicity occurs when they have acquired a given degree of structure, a certain rigid part in the aggregate. This is the first time that a method allows scientists to monitor aggregation while simultaneously detecting a structural pattern responsible for the toxicity of beta-amyloid aggregation.
The scientists state that the medical community can now see structure, organization and the common pattern. Therefore, the hope is that if researchers manage to characterize this pattern, they will be able to look for and design therapeutic molecules that prevent their formation or cause their disruption.
Furthermore, the researchers explain that the tools developed to study beta-amyloid aggregation could be used to examine the aggregation of other proteins that are associated with conditions such as Parkinson’s disease, Huntington’s disease, and type 2 diabetes.