The Brain, Down Syndrome, and Antibiotics
At first glance the title might sound a little weird. But if that is the case then you probably want to read this. Researchers 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 [over other models]. As the title alluded to, 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.
“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.”
For those of you who don’t know, 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 that people are typically born with.
Now mouse models have traditionally been used in studying the genetic disorder, but researchers suggest that the animal model is inadequate because the human brain is more complicated, and much of that complexity arises from astroglial cells, [for those of you who didn’t click the link they are the star-shaped cells in the brain and play an important role in the physical structure of the brain itself, 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.”
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 — or 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 then 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 then 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.
Here is something interesting, 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.”
Researchers 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 the researchers cautioned that its safety and efficacy will require clinical trials in people with Down syndrome.
Currently, the team 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.”
This is just another reason why I love neuroscience so much. With a little luck the antibiotic will show promise when/if it gets to clinical trials. As anyone who has ever done research knows, just because something works in the lab doesn’t mean it will work for people, but that doesn’t keep me from hoping.
Want the full study? Who could blame you! You can find that —here!
Chen, C., Jiang, P., Xue, H., Peterson, S., Tran, H., McCann, A., Parast, M., Li, S., Pleasure, D., Laurent, L., Loring, J., Liu, Y., & Deng, W. (2014). Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells Nature Communications, 5 DOI: 10.1038/ncomms5430