A team of researchers from the Center for Neuroscience and Cell Biology (CNC) of the University of Coimbra (UC) has discovered a possible new therapeutic target for Alzheimer's disease that could represent an important step in the treatment of this neurodegenerative disease.
Currently without effective therapies, Alzheimer's disease is one of the biggest health problems in the world, having a great economic and social impact. It is characterized by the progressive degeneration and death of neurons, especially in the hippocampus, the region of the brain responsible for the formation and consolidation of memories. It is believed that the loss of function of neurons in this region will underlie the memory loss seen in the disease.
Thus, the study, already published in the scientific journal Molecular Therapy – Nucleic Acids, looked for microRNAs (small genetic sequences with a regulatory role in our cells) that were possible innovative therapeutic targets for Alzheimer's disease, having filtered microRNA-31 as a promising target for this type of strategies.
The main objective of this work was «to study whether it would be possible to obtain, through the modulation of a specific microRNA, a beneficial effect in an animal model of Alzheimer's disease. We wanted to see if increasing the levels of microRNA-31 - already identified in lower amounts in the plasma of patients, compared to healthy people of the same age - would bring relevant benefits not only with regard to the histopathological characteristics of the disease, but also in terms of alterations behavioral characteristics of the pathology», says Ana Luísa Cardoso, coordinator of the project.
To assess the beneficial effects of microRNA-31, the team of researchers used a mouse animal model to study Alzheimer's disease, using only females.
After injecting a genetically modified virus that forced the expression of microRNA-31, disease markers were evaluated, such as the accumulation of beta amyloid plaques (toxic clusters of a peptide, characteristic of the disease) in the animals' brains, as well as the loss of neuronal function in the hippocampal zone.
Behavioral tests were also carried out to assess whether microRNA-31 could prevent the memory loss associated with Alzheimer's disease.
«One of the main phases of this study focused on the development of a lentiviral strategy, that is, a virus expression tool, capable of delivering microRNA-31 to neurons and capable of being delivered to the brain of the animal model of the disease. Alzheimer's. Subsequently, we wanted to assess the deposition of beta amyloid plaques, the neuronal function and behavior of animals after microRNA injection, and assess whether there were improvements when compared to animals not treated with the genetic sequence», explains Ana Teresa Viegas, first author of the study.
“We observed that the expression of this microRNA in the hippocampus of animals led to a decrease in the deposition of beta amyloid plaques, especially in the subiculum – the small area of the hippocampus responsible for working memory. We also found that, compared to untreated animals, animals that received microRNA-31 had smaller deficits in this type of memory, which is recruited in simple everyday tasks, not implying several learning processes. At the same time, we observed lower levels of anxiety and cognitive inflexibility – characteristics observed in humans in the early stages of the disease», highlights Ana Teresa Viegas.
The option to carry out the study in female animal models was intended “to show the relevance of focusing some studies on neurodegenerative diseases in females, because, especially in the case of Alzheimer's disease, it is more prevalent in women, and the vast majority of studies are or were made in male animals, ignoring possible differences between sexes.
On the other hand, the study also addressed, in behavioral terms, topics that we have not seen addressed in other studies, such as cognitive inflexibility, with most of them focusing on long-term memory”, says Ana Luísa Cardoso.
In the next phase of the study, the team will seek to understand how the use of this microRNA-31 could be useful for the development of therapeutic strategies for other neurodegenerative diseases and to further explore how this sequence exerts the observed protective effects. It will also study the role of this microRNA in other disease models that are more easily transposable to humans.
This study, which also included the participation of Vítor Carmona, Elisabete Ferreiro, Joana Guedes, Pedro Cunha, Ana Maria Cardoso, Luís Pereira de Almeida, Catarina Resende de Oliveira and João Peça – also CNC researchers – and with the collaboration of João Pedro de Magalhães, researcher at the University of Liverpool, United Kingdom, was funded by the European Regional Development Fund (ERDF), the Foundation for Science and Technology (FCT), Bial and the Marie Curie action programme.
The article, entitled “MiRNA-31 improves cognition and abolishes amyloid-Beta pathology by targeting APP and BACE1 in an animal model of Alzheimer's disease”, can be found at: 10.1016/j.omtn.2020.01.010.
Author: Cristina Pinto (Press Advisory – University of Coimbra – Science Communication
Science in the Regional Press – Ciência Viva
Comments