Cultured 'mini-brains' with Alzheimer's disease help uncover its origins

According to estimates by the Institute of Health Information and Statistics, the number of people suffering from Alzheimer's disease in the Czech Republic will exceed 174,000 in 2030. This will more than double within ten years. The disease, which mainly affects memory and thinking, is still incurable and its origin is unknown. The work of Dr Dáša Bohačiaková's team from Masaryk University's Faculty of Medicine may help to refine existing hypotheses. She and her colleagues are creating so-called cerebral organoids on which they are studying the mechanisms of the disease and testing substances that could prevent its occurrence. Put simply, just as fellow microbiologists guard viruses and bacteria in their laboratories, cell biologists at the medical school have grown miniature brains as small as a few millimetres, even with Alzheimer's disease. Moreover, they are the first in the field to back up their research with single-cell sequencing and can thus support it with unambiguous data.

Among the main pathological features of Alzheimer's disease is amyloid beta, the accumulation of which in brain tissue contributes to neurodegeneration with a number of negative neurological manifestations. Much of the therapeutic focus in recent years has been on reducing it. "Why these clumps are deposited in the brain, we don't know. Nor do we know if amyloid is the cause of the disease or just the result of something else. Even if the amyloid clumps are removed, it doesn't help the patient. The possibility is that such help comes too late, because if Alzheimer's disease starts to form twenty years before a person experiences the first memory problems, then it was necessary to intervene twenty years ago," says Dr Bohačiaková, who has years of experience in studying the molecular mechanisms behind the transformation of stem cells into neurons.

Thanks to them, her team was able to start creating brain organoids on which they model the development of Alzheimer's disease in vitro. The stem cells are obtained from patients with the so-called familial form of the disease, which is genetically determined and makes up a lower percentage of all diagnoses, but manifests much earlier than the predominant sporadic form, typical of elderly patients. "We thought that in order to observe neurodegeneration in our organoid, we would have to let it age. However, the changes started to appear early in its development," Dr Bohačiaková explains the unexpected findings. "This suggests that at least the familial form of Alzheimer's disease is probably related to brain development and that patients have developmental disorders that the body manages to regulate until sometime in their 40s or 50s. So ageing or immunity probably plays only a secondary role in this case."

The aim of Dr. Bohačiaková's team is to uncover the mechanisms of the disease development as early as possible. And on that occasion to establish models or platforms for testing substances that could make Alzheimer's therapies effective in the future. In fact, he and his colleagues have already tested the first therapeutics on grown "mini-mosquitoes". "If we could reduce the amount of amyloids in time, we could extend patients' lives without symptoms of the disease by ten to twenty years, and maybe that would be enough. So maybe we wouldn't have to deal with the root cause," Dr Bohačiaková leaves the door open to further research and suggests what the "Alzheimer's" organoids from Masaryk University Medical School could be used for.