Degeneration of a neuron, conceptual illustration

Researchers at the University of Wisconsin-Madison report that they have identified a protein that allows for the production of norepinephrine neurons from stem cells, a development that has significant implications for research in Alzheimer’s disease (AD), Parkinson’s disease and other psychiatric and other neurodegenerative diseases.

Stem-cell-derived norepinephrine neurons are found in a region of the brain called locus coeruleus and are believed to play a role in the development of AD and Parkinson’s. The new research was published recently in Nature Biotechnology.

Researchers on the project were Yunlong Tao, now an investigator at Nanjing University in China who was a research professor at UW–Madison’s Waisman Center when the study was performed, along with Su-Chun Zhang, a UW–Madison professor of neuroscience and neurology. The researchers call the newly created cells LC-NE neurons and say they could be a valuable new tool for research into ways to treat neurodegenerative diseases.

They note that norepinephrine neurons in the locus coeruleus held regulate heartbeat, blood pressure, arousal, memory, attention and the fight-or-flight response. Humans house around 50,000 of these LC-NE neurons in the hindbrain and from here they reach throughout the brain and spinal cord.

“The norepinephrine neurons in the locus coeruleus are essential for our life. We call it the life center,” Zhang says. “Without these nerve cells, we would probably be extinct from Earth.”

It is known that these neurons play a role in diseases like AD, Parkinson’s, other neurodegenerative conditions and that they start deteriorating early stages of disease, but their exact role in disease development is still unknown. According to Tao, first author of the study, the lack of understanding of the function of the locus coeruleus in this process is not understood in part, because there has not been an adequate model to mimic human LC-NE neurons.

Scientists have previously tried to create the neurons from human stem cells using mouse models, and Tao spent two years to understand why these attempts to develop LC-NE neurons were failing and how development of the neurons from stem cells was different in humans. This research uncovered a growth factor protein called ACTIVIN-A as a key regulator of the neurogenesis of human norepinephrine neurons.

“We have some new understanding about locus coeruleus development,” Tao notes. “That’s the major finding in this paper, and based on that finding, we are able to generate locus coeruleus norepinephrine neurons.”

To create LC-NE neurons, the team converted human pluripotent stem cells into cells from the hindbrain and using ACTIVIN-A and a series of additional signals, to steer cell development toward LC-NE neurons. These converted cells exhibited the characteristics and function of LC-NE neurons in the human brain typified by the release of norepinephrine. The cells also exhibited axonal arborization—the growth of branching arms of neurons that allow the connection of brain cells—and also reacted to the presence of carbon dioxide which helps them regulate breathing.

The hope is that these new cells can serve as study models for screening new potential drugs for the treatment of a range of neurodegenerative diseases, as well as allow for a better understanding of why locus coeruleus cells die so early in the development of these conditions.

“If this is somewhat causative, then we could potentially do something to prevent or delay the neurodegeneration process,” Zhang says.

Next steps in the research will be to examine the detailed mechanisms through which ACTIVIN-A regulates LC-NE neuron development and use the cells for the translational work of drug screening and disease modeling.

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