Mini brain with BASS/LVD
Amyotrophic lateral sclerosis is a disease in which motor neurons suffer and which affects people aged 40-45 years. It can be combined with frontotemporal dementia (ALS/LVD). ALS/LVD is manifested by progressive muscle weakness and irreversible changes in memory, behavior and personality. The creation of reduced organ-like models (organoids) of the brain will provide researchers with a tool for studying the course of ALS/LVD at the earliest stages, long before the onset of symptoms and testing potential drugs.
A group of scientists from the John van Geest Brain Recovery Center at the University of Cambridge used stem cells obtained from patients with ALS/LVD to grow organoids that mimic the human cerebral cortex in terms of stages of embryonic development, 3D architecture, a variety of cell types and intercellular interactions.
The new organoids will help to see what happens in the early stages of the disease long before the first symptoms appear and how different brain cells change over time.
These are not the first brain organoids with a neurodegenerative disease, but in previous models, efforts were often directed at growing them within a relatively short period of time, which limits the range of disorders that can be recreated. In an earlier work, Cambridge researchers grew organoids with BAS/LVD for 340 days, and now they were able to achieve the same result in a shorter time – 240 days.
Another feature of the new organoids is a special architecture – the cells in them are grouped not in the form of a sphere, but in the form of layered sections. In spherical organoids, cells located closer to the center do not receive sufficient nutrition, which may explain why previous attempts at long-term organoid cultivation from patients' cells were unsuccessful.
Using the new organoids, the researchers reproduced and observed changes occurring in cells at a very early stage of ALS/LVD, including cellular stress, DNA damage and transcription disorders. These processes affected neurons and astrocytic glia – brain cells that control muscle movements and cognitive abilities.
Although these first disturbances were minor, the researchers were surprised by how early they occurred in the ALS/LVD model. This and other recent studies demonstrate that damage can accumulate from birth. To understand whether this hypothesis is true, or whether this process is caused in organoids by artificial conditions in the laboratory, further research is needed.
In addition, organoids can be a powerful tool for screening potential medications to determine which ones can prevent or slow the progression of ALS/LVD. This is the most important advantage of organoids, since animal models often do not show the characteristic changes associated with the disease.
The group showed that the drug GSK2606414 is effective for eliminating characteristic cellular disorders in ALS/LVD, including the accumulation of toxic proteins, cellular stress and death of nerve cells, which blocks one of the pathways contributing to the disease. Similar drugs that are more suitable as medications and approved for use in humans are currently undergoing clinical trials for the treatment of neurodegenerative diseases. By simulating some of the mechanisms that lead to DNA damage in nerve cells, researchers will be able to identify potential targets for future drugs with the help of new organoids.
Article by K.Szebényi et al. Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targeted neuronal pathology published in the journal Nature Neuroscience.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the University of Cambridge: Lab-grown 'mini brains' hint at treatments for neurodegenerative diseases.