New genetic clues to early-onset form of dementia

December 13, 2018

Unlike the more common Alzheimer's disease, frontotemporal dementia tends to afflict young people. It accounts for an estimated 20 percent of all cases of early-onset dementia. Patients with the illness typically begin to suffer memory loss by their early 60s, but it can affect some people as young as their 40s, and there are no effective treatments.

In an effort to better understand the condition, an international team of researchers, led by Washington University School of Medicine in St. Louis, has found that a lone mutation in a single gene that causes an inherited form of frontotemporal dementia makes it harder for neurons in the brain to communicate with one another, leading to neurodegeneration.

The new findings zero in on the MAPT gene. That gene makes a protein called tau, which also has been associated with cognitive decline in Alzheimer's disease. Identifying the downstream effects of the mutation could help identify new treatment targets for frontotemporal dementia, Alzheimer's disease and other tau-related illnesses, including Parkinson's disease.

The study is published Dec. 13 in the journal Translational Psychiatry.

"We have demonstrated that we can capture changes in human cells cultured in a dish that also are appearing in the brains of individuals suffering with frontotemporal dementia," said Celeste M. Karch, PhD, an assistant professor of psychiatry and one of the study's senior authors. "Importantly, the approach we are using allows us to zero in on genes and pathways that are altered in cells and in patient brains that may be influenced by compounds already approved by the FDA. We want to evaluate whether any of these compounds could prevent memory loss, or even restore memory, in people with frontotemporal dementia by improving the function of these pathways that have been disrupted."

Karch, with co-senior author Carlos Cruchaga, PhD, an associate professor of psychiatry, and the other co-senior author, Oscar Harari, PhD, an assistant professor of psychiatry, gathered skin samples from patients with frontotemporal dementia who were known to have a specific mutation in the MAPT gene.

The researchers then converted the patients' skin cells into induced pluripotent stem cells, which have the ability to grow and develop into any cell type in the body. The researchers treated these stem cells with compounds that coaxed them to grow and develop into neurons, which also had the MAPT mutation. Then, using gene-editing technology called CRISPR, the researchers eliminated the mutation in some neurons but not others and observed what happened.

"We found differences in genes and pathways related to cellular communication, suggesting the mutation alters neurons' ability to communicate," said Cruchaga. "The initial mutation in MAPT is the key change that starts the disease, and it is a potential target for therapy, but there are other genes downstream from the MAPT gene that also are good targets that may be used to treat the disease."

In neurons with the mutation, the researchers found alterations in 61 genes, including genes that make GABA receptors on brain neurons. GABA receptors are the major inhibitory receptors in the brain, and they are key to several types of communication between brain cells.

The researchers identified similar disruptions in genes that make GABA receptors when they did experiments in animal models and analyzed brain tissue from patients who had died with frontotemporal dementia. They also looked at findings from a genomewide association study of more than 2,000 patients with frontotemporal dementia and more than 4,000 without the disorder. That analysis also pointed to GABA-related genes as potential targets.

"Using our stem cell-derived neurons, we have the opportunity, in human tissue, to target some of those GABA genes in advance of the neurodegeneration we see in the postmortem tissue we study," said Harari. "So, at least in cell cultures, we can learn whether potential therapies prevent the damage caused by inherited forms of frontotemporal dementia."

And by studying rare, inherited forms of brain diseases, the researchers believe they will learn a great deal about how to treat the more common forms of those disorders.

"Genetic forms of frontotemporal dementia and Alzheimer's disease are caused by rare mutations," Cruchaga said. "But they have much in common with the more typical cases of those diseases. If we understand these cases caused by inherited mutations, we also should better understand the common forms of these diseases."
-end-
Jiang S, et al. Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP. Translational Psychiatry, published online Dec. 13, 2018.

This work was supported by the National Institute on Aging of the National Institutes of Health (NIH). Grant numbers K01 AG046374, R01 AG056923, R01 AG044546, P01 AG003991, RF1 AG053303, R01 AG052501, U01 AG05241102, U01AG058922, P50 AGB05681, P01 AG03991and P01 AG026276, and the Dominantly Inherited Alzheimer's Network, DIAN UF1AG032438. Additional funding from the Tau Consortium, the Alzheimer Association, the German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, the Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D project through the Korea Health Industry Development Institute.

Washington University School of Medicine's 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University School of Medicine

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.