Big dynorphin protects neurons from the accumulation of ß-amyloid, one of the main triggers of Alzheimer's disease

A study coordinated by the UAB, based on computer models and human cell cultures, shows that big dynorphin, an endogenous opioid peptide, protects neurons against the cytotoxic effects of β-amyloid accumulation.

One of the main features of Alzheimer's disease is that the β-amyloid peptide, a molecule found inside neurons that has many diverse functions, begins to fold incorrectly and accumulates. This process, which ends up causing neurons death, is linked to a series of other cellular alterations, which are often difficult to determine if whether they are the cause or the consequence. An example is the case of the deregulation of a type of dynorphin.

Dynorphins are the body's own opioid peptides, which play a key role in many brain pathways. They are located in different areas of the brain, such as the hippocampus, amygdala or hypothalamus, and are involved in memory processes, emotion control, stress and pain, and among other processes. In addition, several studies have shown its their involvement in epilepsy, stroke, addictions, depression or and schizophrenia.

Now, in a study published in the Computational and Structural Biotechnology Journal, a research group led by Àlex Perálvarez-Marín, researcher in the Department of Biochemistry and Molecular Biology and the UAB Institut de Neurociències, has studied from computer models and cell cultures what interactions may exist between β-amyloid peptide and big dynorphin, to determine its role in β-amyloid accumulation.

"The β-amyloid peptide is negatively charged and, on the other hand,while dynorphins are positively charged. Since the positive interacts with the negative, and we knew that both peptides are located in the same place, we thought it could would be interesting to study the two molecules together", explains Dr Perálvarez-Marín.

The results show that, due to the physico-chemical features of big dynorphin, its presence hinders the amyloid interaction and the formation of β-amyloid peptide aggregates, apart fromin addition to promoting a neuroprotective effect. In additionMoreover, thanks to computational modeling, researchers could were able to obtain clues about which big dynorphin regions interact with the β-amyloid peptide. "From a basic research perspective, the study opens a therapeutical intervention window against Alzheimer's disease, where the design of therapeutic peptides could represent an advance to stop amyloid aggregation phenomena", concludes Dr Perálvarez-Marín.

The article proposes new approaches in the search for treatments for Alzheimer's disease using therapeutic peptides based on big dynorphin, and proposes suggests to exploreing the specific advantages of an endogenous neuropeptide, capable of crossing the blood-brain barrier to reach the brain and prevent amyloid aggregation.

Image: The research team at the INc-UAB. Alex Perálvarez-Marín is the third from the left. (INc-UAB)

Reference: Lucía Gallego-Villarejo, Cecilia Wallin, Sylwia Król, Jennifer Enrich-Bengoa, Albert Suades, Marcel Aguilella-Arzo, María José Gomara, Isabel Haro, Sebastian Wärmlander, Francisco J Muñoz, Astrid Gräslund, Alex Perálvarez-Marín. Big dynorphin is a neuroprotective scaffold against amyloid β-peptide aggregation and cell toxicity Comput Struct Biotechnol J. 2022 Oct 14;20:5672-5679. doi: 10.1016/j.csbj.2022.10.014. eCollection 2022.