astrogliosis

‘Support cells’ in brain play important role in Down syndrome

Researchers from UC Davis School of Medicine and Shriners Hospitals for Children – Northern California have identified a group of cells in the brain that they say plays an important role in the abnormal neuron development in Down syndrome. After developing a new model for studying the syndrome using patient-derived stem cells, the scientists also found that applying an inexpensive antibiotic to the cells appears to correct many abnormalities in the interaction between the cells and developing neurons.

The findings, which focused on support cells in the brain called astroglial cells, appear online today in Nature Communications.

“We have developed a human cellular model for studying brain development in Down syndrome that allows us to carry out detailed physiological studies and screen possible new therapies,” said Wenbin Deng, associate professor of biochemistry and molecular medicine and principal investigator of the study. “This model is more realistic than traditional animal models because it is derived from a patient’s own cells.”

Down syndrome is the most common chromosomal cause of mild to moderate intellectual disabilities in the United States, where it occurs in one in every 691 live births. It develops when a person has three copies of the 21st chromosome instead of the normal two. While mouse models have traditionally been used in studying the genetic disorder, Deng said the animal model is inadequate because the human brain is more complicated, and much of that complexity arises from astroglia cells, the star-shaped cells that play an important role in the physical structure of the brain as well as in the transmission of nerve impulses.

“Although neurons are regarded as our ‘thinking cells,’ the astroglia have an extremely important supportive role,” said Deng. “Astroglial function is increasingly recognized as a critical factor in neuronal dysfunction in the brain, and this is the first study to show its importance in Down syndrome.”

Creating a unique human cellular model

To investigate the role of astroglia in Down syndrome, the research team took skin cells from individuals with Down syndrome and transformed them into stem cells, which are known as induced pluripotent stem cells (iPSC). The cells possess the same genetic make-up as the donor and an ability to grow into different cell types. Deng and his colleagues next induced the stem cells to develop into separate pure populations of astroglial cells and neurons. This allowed them to systematically analyze factors expressed by the astroglia and then study their effects on neuron development.

They found that a certain protein, known as S100B, is markedly increased in astroglial cells from patients with Down syndrome compared with those from healthy controls. S100B released by astroglial cells promotes harmful astroglial activation (astrogliosis) and adversely affects neurons, causing them to die at increased rates or develop in multiple dysfunctional ways.

The investigators obtained further evidence of the critical role of astroglial cells in Down syndrome by implanting the skin-cell derived astroglial cells from Down syndrome patients into mice. Those mice then developed the neuropathological phenotypes of Down syndrome, while mice implanted with Down syndrome neurons did not.

Neuroprotective effects of antibiotics

The research team also screened candidate drugs using a ‘disease-in-a-dish’ model. When they administered minocycline — a tetracycline antibiotic with anti-inflammatory properties commonly used to treat bacterial infections, acne and arthritis — many of the abnormalities in the astroglial cells were corrected and there were more healthy interactions between the astroglia and neurons compared to the control cells without the defect.

“The advent of induced pluripotent stem cell technology has created exciting new approaches to model neurodevelopmental and neurodegenerative diseases for the study of pathogenesis and for drug screening,” said David Pleasure, professor of neurology and pediatrics and a co-author of the study. “Using this technology, the study is the first to discover the critical role of astroglial cells in Down syndrome as well as identify a promising pathway for exploring how a drug such as minocycline may offer an effective way to help treat it.”

Pleasure, who is research director at Shriner’s Hospital for Children Northern California and also directs the Institute for Pediatric Regenerative Medicine, noted that considerable research interest has arisen about the use of minocycline for diseases of the central nervous system because of the increasing evidence about its neuroprotective effects. Unlike many drugs, minocycline can cross from the bloodstream into the brain so that it can act on the astroglial cells. The drug has never been tested as a treatment for Down syndrome, and both Pleasure and Deng cautioned that its safety and efficacy will require clinical trials in people with Down syndrome.

Currently, Deng’s laboratory is conducting additional preclinical studies using the human-derived stem cells from Down syndrome patients and mouse models to determine whether cellular and behavioral abnormalities can be improved with minocycline therapy and other candidate drugs.

“The abnormalities we identified occur in the early stages of Down syndrome,” said Deng. “While much more research is needed, it is exciting to consider that pharmacological intervention in these cellular processes might help slow or even prevent disease progression.”

(Image: iStockphoto)

Not enough YAP means too much deadly inflammation inside the brain

Inside the brain, a protein called YAP, best known for its ability to help right-size our developing hearts and livers, appears to have the different but equally important task of helping control inflammation.

Scientists at the Medical College of Georgia at Augusta University have shown that it’s not size that seems to matter to YAP, or yes-associated protein, in the brain. Rather, YAP keeps our astrocytes, a type of brain cell that typically protects and nourishes neurons, from becoming too reactive and essentially turning on our neurons.

“While these YAP normally control organ size, in the brain, YAP influences astrocyte function, which, in turn, helps regulate our protective blood-brain barrier function,” said Dr. Wen-Cheng Xiong, developmental neurobiologist and Weiss Research Professor at MCG.

In the body, YAP helps control the size of our major organs by regulating cell death and proliferation. But, Xiong and her colleagues found that inside the developing brain, YAP is a critical inducer of suppressor of cytokine signaling 3, or SOCS3, another protein, which as the name implies, suppresses inflammation-provoking immune cells. Inflammation can be dangerous even deadly in the closed confines of the skull, where resulting swelling and pressure can destroy neurons, said Xiong, corresponding author of the study in the journal Cerebral Cortex.

Xiong suspects that in conditions, such as hemorrhagic - or bleeding - stroke and hydrocephalus, where fluid accumulates inside the skull of a baby or an adult in response to injury, a problem with YAP could be a factor.

In fact in her studies, mice missing YAP also had a form of hydrocephalus that at first made Xiong suspect that YAP did help control the size of the brain. However, when the scientists dissected the too-large organ, they found it was mostly fluid. And the mice missing YAP did not induce SOCS3. “The brake is gone and over-inflammation can occur,” she said.

YAP is expressed in both astrocytes as well as the neural stem cells that help make more astrocytes and, to a lesser extent, neurons, for the brain. Xiong and her team found that without YAP, astrocytes became hyper-reactive, creating a condition called astrogliosis where they weaken instead of strengthen the important but fragile blood-brain barrier.  

The blood-brain barrier is essentially a layer of tightly knit endothelial cells that line blood vessels in the brain, a single layer of smooth muscle cells, or pericytes, on top of that, and a layer of astrocytes on the exterior. The unique configuration in the blood vessels of the brain and spinal cord create a fine filter that limits what substances can get access to brain tissue from the blood.

“The blood-brain barrier is completely disrupted in hemorrhagic stroke,” Xiong said. “Once that is broken, it changes everything.” Cell types and factors that normally don’t have access to the brain confuse the relationships between cell types and substances that are usually there. One consequence is that fluid from the blood also gets into brain tissue, adding pressure to the confused conversations. Neurons start to die, scar tissue forms and more astrocytes form.

They found levels of several SOCS proteins were lower in mice where the YAP gene was deleted from the brain. To double-check the connection between SOCS3 and YAP, they selectively expressed SOCS3 in the astrocytes of the YAP knockouts and still found less inflammation. The inflammation also seemed to focus on the blood vessels in mice missing YAP, and when they injected a dye tracer that normally cannot penetrate the blood-brain barrier, it easily penetrated into the brains of mice missing Yap from their astrocytes.  

Xiong wants to pursue studies examining the blood of newborns with hydrocephalus for signs of mutated YAP. A mutant form of YAP is known to cause liver cancer, in which cells just keep growing, and the Hippo signaling pathway that activates YAP has been targeted for its anti-cancer potential.