A team of CNC researchers uncovered a possible new therapeutic target for Alzheimer’s disease, which could impose as an important step for the treatment of this neurodegenerative disease.
Currently without effective therapies, Alzheimer’s disease is one of the world’s biggest health problems, with huge social and economic impacts. It is characterized by the progressive degeneration and death of neurons, especially in the hippocampus, the brain region responsible for memory formation and consolidation. It is believed that the loss of neuronal function in this region is the main cause for the memory loss observed in this disease.
This way, the study already published in the scientific journal Molecular Therapy – Nucleic Acids searched for microRNAs (little genetic sequences with a regulatory role in our cells) that could be possible innovative therapeutic targets for Alzheimer’s disease, having filtered the microRNA-31 as a promising target for this kind of strategies.
This work had the main goal of “study if it would be possible, my modulating a specific microRNA, a beneficial effect in an animal model of Alzheimer’s disease. We wanted to observe if by increasing the levels of microRNA-31 – already described to be in low levels in the plasma of patients – would bring relevant benefits, not only in regard to the histopathological aspects of the disease, as well as the behavior changes also characteristic of this disease”, affirms Ana Luísa Cardoso, project coordinator.
To evaluate the beneficial effects of microRNA-31, the research team used an animal model for Alzheimer’s disease, only using females. After injecting a genetically modified virus that would force the expression of microRNA-31, the researchers then evaluated markers of the disease, such as the accumulation of beta-amyloid plaques (toxic agglomerates of a peptide, characteristic of this disease) in the brain of animals, as well as the loss of neuronal function in their hippocampus. They also conducted behavioral assays, to determine if microRNA-31 could prevent the memory loss associated with Alzheimer’s.
“One of the main stages of this study focused on the development of a lentiviral strategy, or, a viral expression tool, which could deliver microRNA-31 to neurons. Afterwards, we wanted to evaluate the deposition of beta-amyloid plaques, the neuronal function, and animal behavior after microRNA injection, assessing possible improvements, comparing to the animals not treated with that genetic sequence”, explain Ana Teresa Viegas, first author of the study.
“We observed that the expression of the microRNA in the hippocampus of these animals led to a decrease in the deposition of beta-amyloid plaques, especially in the subiculum region – a small hippocampal region responsible for working memory. We also verified that, comparing to non-treated animals, the animals who received microRNA-31 would present less deficits in this type of memory, which is recruited in simples daily-life tasks, not implying learning processes. Simultaneously, we observed less levels of anxiety and cognitive inflexibility – a observed characteristic of humans in the early stages of the disease”, highlight Ana Teresa Viegas.
The option to conduct the study in female animal models was meant to “show the relevance of focusing some studies on neurodegenerative disorders on the female sex, because, especially in Alzheimer’s disease context, this is a much more prevalent disorder in women, and most studies are, or were made, in male animals, disregarding possible sex differences. On the other hand, the study also approached other topics, in behavior, which we have not seen covered in other studies, such as cognitive inflexibility, as most of them only focus on long-term memory”, concludes Ana Luísa Cardoso.
In the next step 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 disorders, and to better explore how this sequence exerts its observed protective effects. It will also study other roles for this microRNA in other animal models for this disease, which could be more easily compared to humans.
This study, which also had 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 a collaboration with João Pedro de Magalhães, researcher at Liverpool University, United Kingdom, was financed by the European Fund for Regional Development (FEDER), by the Foundation for Science and Technology (FCT), by Bial, and by the Marie Curie Action program.
The study, 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 consulted in: 10.1016/j.omtn.2020.01.010.
Credits: Ana Luísa Cardoso, Ana Teresa Viegas, Cristina Pinto, João Cardoso