New culture of human neurons could help bring Alzheimer's disease under control

Testing various therapies for neurodegenerative diseases is possible either on model animals - genetically modified mice - or on human cell culture. In the first case, the success of the experiment does not necessarily mean that the drug will be safe and effective for humans. In the second case, it takes a very long time to "mature" neurons to a state similar to the age of cells in the brain of most patients with neurodegenerative conditions. A new model cell culture created in the USA solves exactly this problem.

A significant proportion of all neurodegenerative diseases involve disruption of the "normal function" of the tau protein (MAPT), a key element of the neuronal cytoskeleton. Such diseases are called taupathies. They include Alzheimer's and Pick's diseases, progressive supranuclear gaze paresis, and corticobasal degeneration.

For a number of reasons, most commonly with age, excessive phosphorylation of tau protein and its isoforms occurs in cells. As a result, MAPT forms neurofibrillary tubules rather than cytoskeletal microtubules. These structures gradually disrupt normal neuronal viability and, along with other disease-specific pathologic changes, lead to systemic loss of nervous system function.

A serious obstacle to the study of these processes is their slowness. In model organisms and human cell cultures, the formation of a characteristic pattern of neurodegenerative disease takes many months. With mice, such a period can still be accepted: after all, scientists have long been accustomed to keep whole broods of experimental animals in varying degrees of readiness for experimentation. Yes, it is not cheap and troublesome, besides the results are not always transferred to humans. But the technology has been worked out and has good results.

But to grow, control and maintain cell culture in strictly defined conditions for the same long time is a whole project of considerable complexity. Especially when it comes to expensive cultures of human stem cells. But the results are much more valuable in terms of medicine. In general, there is no perfect solution, they are all problematic.

There is another limitation: human pluripotent stem cells (hiPSC), specialized into neurons, produce very few 4R-isoforms of tau-protein. And they are particularly important for studying the many subtleties of pathological processes associated with neurodegenerative diseases. Simply put, in order to find the most effective methods to restrain taupathia, it is necessary to cultivate cells not for months, but for years or even decades - otherwise a sufficient number of 4R-isoforms in neurons will simply not accumulate. Naturally, this approach is unnecessarily complicated and expensive.

A new cell culture carrying the P301S mutation in the gene responsible for the production of tau-protein should come to the rescue. These are genetically modified human pluripotent stem cells specialized into neurons that produce increased amounts of MAPT. They are able to accumulate the necessary amounts of different isoforms of this protein, including 4R, in a matter of weeks.

To further improve the result, American researchers, using CRISPR interference (selective "switching off" genes), screened thousands of genes and assessed their impact on the production of tau-protein. In total, the scientists were able to identify 500 genes that contribute to this process.

One of the promising discoveries made in the described scientific publication is the role of the UFM1 protein, and more precisely - the cascade of its interactions with other molecules in neurons. Earlier in the brains of deceased patients with Alzheimer's disease were found violations of the "work" of UFM1, but the process was not studied in detail. Now scientists have clearly seen: to inhibit the spread of tau-proteins in the cell, it is enough to block the enzyme necessary for the functioning of the UFM1-cascade.

The new cell culture was developed by specialists from the Weill Cornell Medical College of Cornell University (Weill Cornell Medicine) with the participation of colleagues from leading research and medical institutions in the United States and Canada. A scientific paper describing the methodology of creating a new cell culture of human neurons and the results of experiments to test the targets for therapy of neurodegenerative diseases was published in the peer-reviewed journal Cell.