They manage to rejuvenate neurons in the brain

Scientists have managed to rejuvenate neurons in the brain through cellular reprogramming.

The achievement is the work of a team made up of, among others, Sofia Zaballa, Daniel del Toro and Albert Giralt, from the University of Barcelona (UB); Manuel Serrano, from the Barcelona Biomedical Research Institute (IRB Barcelona); as well as Yi-Ru Shen and Rüdiger Klein, from the Max Planck Institute for Biological Intelligence in Germany.

When a neuron ages, it loses synaptic connections with other neurons, has less capacity to transmit nerve impulses, and its metabolism is also altered. This process of neuronal aging—inevitable over time—is especially accelerated and becomes a risk factor in neurodegenerative pathologies such as Alzheimer’s disease. But can the effects of aging in cells as specialized as neurons be reversed?

The new research has made it possible to find out how brain neurons in mice can be rejuvenated through a cycle of controlled cellular reprogramming that helps recover some altered neurological properties and functions. What was discovered in this study could open new perspectives for studying neurodegenerative diseases in patients.

Among other things, the study has devoted special attention to the role played by what is known as Yamanaka factors, a series of proteins that are key to reversing aging and that have been little studied until now in the nervous system.

In 2012, Japanese scientist Shinya Yamanaka and British scientist John Gurdon received the Nobel Prize in Medicine for research to reprogram differentiated cells and return them to a state typical of pluripotent cells. Yamanaka factors—specifically Oct4, Sox2, Klf4, and c-Myc—are transcription factors present throughout the scientific literature on cellular reprogramming.

Although much of the international research has focused on the study of the factors in the rejuvenation and regeneration of peripheral tissues (skin, muscle, liver and heart), now the new work delves into the effects that they could cause in the central nervous system.

Specifically, the team has studied the effects of controlled expression of Yamanaka factors in the brain of mice in cycles of cellular reprogramming throughout different phases of neuronal development.

Daniel del Toro, principal investigator of the Ramón y Cajal program in the Department of Biomedicine of the UB, emphasizes that, “when Yamanaka factors are introduced during the development phase, more neurons are generated and the brain is more voluminous (it can reach to be twice as big). This translates into better motor and social activity in adult stages. These results are explained because we made all brain cells able to express these factors, which also includes stem cells. It was very surprising to discover that, if we control the expression of these factors very precisely, we are also able to control the process of cell proliferation and obtain brains with a larger cerebral cortex and without losing the correct structure and functions,” he adds.

The researcher admits that “we were also surprised to see that, in terms of behavior, there were no negative behavioral consequences, and the mice even improved in motor behaviors and social interaction.”

For his part, Professor Albert Giralt specified that, in the case of adult mice, “the expression of Yamanaka factors in adult neurons causes these cells to rejuvenate and show protection against neurodegenerative diseases such as Alzheimer’s.” «In this case, what we did is induce the expression of Yamanaka factors only in mature neurons. Since these cells do not divide, their number does not increase, but we identified many markers that indicate a process of neuronal rejuvenation. In these rejuvenated neurons, we detect that the number of synaptic connections increases, the altered metabolism is stabilized and the epigenetic profile of the cell is also normalized,” Giralt details. “This whole set of changes has a very positive effect on their functionality as neurons,” says the expert.

The controlled expression of Yamanaka factors allows obtaining brains with a larger cerebral cortex. (Image: Cell Stem Cell. CC BY)

Cell reprogramming to fight neurodegenerative diseases

Understanding the aging process on a cellular scale opens new horizons in the fight against diseases through cellular reprogramming. However, this process also carries the risk of generating the growth of aberrant populations of cells, that is, tumors.

The experts detail that “in our study, and through precise control in specific neural populations, we have achieved that the factors are not only safe, but also improve neuronal synaptic plasticity as well as higher-order cognitive functions, such as ability to socialize and form new memories. Likewise, they emphasize that, “as positive effects have also been identified when factors are expressed in very early stages of brain development, we consider that it would be interesting to explore their consequences in neurodevelopmental disorders.”

Now, how do these factors act on the nervous system? Everything indicates that the Yamanaka factors act on at least three molecular scales. Firstly, they have epigenetic effects and this would influence gene transcription (DNA methylation process, histones, etc.). It would also compromise metabolic pathways and mitochondrial function (production and regulation of cellular energy). Finally, they could impact many genes and signaling pathways involved in synaptic plasticity.

In summary, the new study expands the knowledge on the functions of the Yamanaka factors described so far.

The study is titled “Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming.” And it has been published in the academic journal Cell Stem Cell.

The researchers now plan future research to determine which other diseases of the nervous system could benefit from cell reprogramming technology, delve into the underlying molecular mechanisms to design new therapeutic strategies and, finally, bring the results closer to clinical practice in treatment. to patients.” (Source: UB)