Frontotemporal dementia is a rare form of dementia that usually begins between ages 40 and 60. It affects the front and side (temporal) areas of the brain, leading to behavior changes and difficulty with speaking and thinking.
The study was led by Kathryn Bowles, PhD, an instructor in Dr. Goate’s lab at Mount Sinai. Working with scientists at the Neural Stem Cell Institute (NSCI) in Rensselaer, New York, Washington University in St. Louis, Missouri, Massachusetts General Hospital in Boston, and the University of Southern California, Los Angeles, the researchers created thousands of cerebral organoids from induced pluripotent stem cells (iPSCs).
Induced pluripotent stem cells are created by genetically and chemically reprogramming a person’s skin or blood cells into newborn stem cells, which have the potential to become any cell in the body. From these stem cells, the NSCI created thousands of tiny, 3D cerebral organoids, which mimic the early growth and development of the cerebral cortex for intensive study by collaborating scientific groups.
“Induced pluripotent stem cells are powerful tools. They allow researchers to study each patient’s personalized disease in a petri dish,” said Sally Temple, PhD, Scientific Director of the NSCI and a senior author of the study. “In this study we were able to take this idea to the next level. By combining iPSC-organoid technology with high-throughput, single cell gene activity analysis, we were able to get a better look at what might be going on in a patient’s brain at early stages of disease development, even before symptoms emerge.”
In this study, the researchers examined the growth and development of organoids derived from the stem cells of three patients, all of whom carried the V337M mutation in tau. They then compared their results with those observed in “isogenic,” control organoids. The controls were derived from patient stem cells in which the disease-causing mutation was genetically corrected.
After six months of growth, signs of neurodegeneration were seen in the organoids. Most notably, the patient-derived organoids had fewer excitatory neurons than those derived from the control cells, demonstrating that the tau mutation was sufficient to cause higher levels of cell death of this specific class of neurons. Excitatory neurons usually fire in response to the neurochemical glutamate and are known to die at abnormally high levels in frontotemporal dementia. The patient-derived organoids also had higher levels of harmful versions of tau protein and elevated levels of inflammation.
“Excitatory neuron cell death, tau protein deposits, and inflammation are classic hallmarks of the kind of damage seen in many forms of frontotemporal dementia,” said Dr. Bowles. “What we wanted to know next was: what are the cellular and molecular processes that occur before the appearance of these disease hallmarks?”