Peptides are naturally occurring biological molecules that are short chains of amino acid monomers linked by peptide (amide) bonds. They differ from proteins mainly in the number of amino acids contained within each molecule, so they are shorter.
The peptide beta-amyloid (Aβ) 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
In a study conducted by Scientists at the Institute for Research on Biomedicine (IRB) Barcelona in collaboration with researchers at the University of Barcelona, it was observed that aggregates of 20 to 100 units of beta-amyloid have a structure that is the most harmful to neurons. The method used allowed scientists to monitor and distinguish different types of aggregations for the first time. While simultaneously, they were able to detect a structural pattern responsible for the toxicity of Aβ aggregation.
Those aggregates formed by 20 to 100 units of Aβ are known as intermediate aggregates or precursor aggregates of beta-amyloid fibrils. In contrast, Aβ aggregates and the amyloid fibrils, which can contain up to 3,000 units of the peptide, do not cause neuronal death.
To determine this, the scientists treated cultures of mouse neurons with samples obtained at different times of the Aβ 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. They prepared the neuronal cultures from the hippocampus, the brain region in which neuronal lost is first observed in Alzheimer’s disease.
Natàlia Carulla, scientist at the Institute for Research in Biomedicine (IRB Barcelona) and principal investigator of the study said: “The technique that we have set up allows us to detect how the structure within these aggregates increases, that is to say, how the aggregates take shape and how they get organized. We observed that maximum toxicity occurs when they have acquired a given degree of structure, a certain rigid part in the aggregate,”
The work published in the scientific journal ACS Chemical Biology 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.
First author of the article Bernat Serra-Vidal, whose PhD thesis was based on this work explain that now they are able to see the structure, organization and common pattern of Aβ aggregation. Therefore, if they manage to characterize this pattern, they will be able to look for and design therapeutic molecules that prevent their formation or cause their disruption to treat Alzheimer’s disease.
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.
Through: Institute for Research on Biomedicine (IRB) Barcelona / Agencia ID
