Dementia is a general term for a group of diseases that impair memory, thinking, or decision-making and interfere with everyday activities. According to the World Health Organization (WHO), around 50 million people worldwide have dementia, with nearly 10 million new cases every year. Although it primarily affects older people, it is not a normal part of aging. As our population ages its critical to better understand why this occurs.
Frontotemporal dementia
Frontotemporal dementia is a rare form of dementia where people start to show signs between the ages of 40 and 60. It affects the front and side (temporal) areas of the brain, hence the name. It leads to behavioral changes and difficulty with speaking and thinking. This form of the disease is caused by a genetic mutation called tau, which is known to be associated with Alzheimer’s disease and other dementias.
A CIRM-supported study using induced pluripotent stem cells (iPSCs) led by Kathryn Bowles, Ph.D., and conducted by a team of researchers at Mount Sinai was able to recreate much of the damage seen in a widely studied form of frontotemporal dementia by growing special types of ‘mini-brains’, also known as cerebral organoids.
Mini-brains and research
iPSCs are a type of stem cell that can be created from skin or blood cells through reprogramming and can turn into virtually any other kind of cell. The team used iPSCs to create thousands of tiny, 3D ‘mini-brains’, which mimic the early growth and development of the brain.
The researchers examined the growth and development of these ‘mini-brains’ using stem cells derived from three patients, all of whom carried a mutation in tau. They then compared their results with those observed in “normal” mini-brains, which were derived from patient stem cells in which the disease-causing mutation was genetically corrected.
After six months, signs of neurodegeneration were seen in the patient ‘mini-brains’. The patient-derived ‘mini-brains’ had fewer excitatory neurons than the “normal” ones, showing that the tau mutation was sufficient to cause higher levels of cell death in this specific class of neurons. Additionally, the patient-derived ‘mini-brains’ had higher levels of harmful forms of tau protein and elevated inflammation.
In a news release from Mount Sinai, Dr. Bowles elaborated on the study’s results.
“Our results suggest that the V337M mutant tau sets off a vicious cycle in the brain that puts excitatory neurons under great stress. It hastens the production of new proteins needed for maturation but prevents disposal of the proteins that are being replaced.”
The full results of this study were published in Cell.