The study, published in Science Translational Medicine on November 18, revealed two important new findings about Down's syndrome in a mouse model: 1) there is evidence that synaptic terminals involved in neurotransmission are damaged long before the cells show degeneration; and 2) while cell signaling is damaged, the receptors are not, but are functioning and still trying to find signals.
"If we focus only on damage to cell bodies, we underestimate the importance of timing and the potential window for treatment of Down's syndrome," said Mobley, one of the nation's leading experts in the disease. He added that this study in mice shows some of the early changes to neurons, which are "really quite dramatic," and may point the way to novel ways to treat Down's syndrome in adult patients.
Down's syndrome is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome, resulting in marked deficits in contextual learning and memory. Fifty years ago, the disorder was identified as a chromosome 21 trisomy, meaning that each cell in the body has three copies of chromosome 21 instead of the usual two.
Individuals with Down's syndrome tend to have a lower than average cognitive ability, and most who survive into middle age begin to show Alzheimer's-like dementia by age 50 or 60. The incidence of Down's syndrome is estimated at one in 733 live births in the U.S., or 5,000 affected infants each year; approximately 95% of these are trisomy 21. Until quite recently, it wasn't believed that scientists would ever be able to pinpoint the exact gene or genes that cause the disease.
The research team studied a mouse model with three copies of a fragment of mouse chromosome 16, having symptoms very similar to those in humans with Down's syndrome. Symptoms included significant cognitive deficits and dysfunction and degeneration of LC neurons (with origination in locus coeruleus). These damaged neurons use norepinephrine, which is a neurotransmitter, to pass impulses to receptors in the cortex and hippocampus – brain regions critical for learning, memory and attention.
"We found that, despite advanced LC degeneration, we could reverse contextual learning failure in these mice," said Mobley. Using a pro-drug for norepinephrine called L-DOPS or xamoterol, the scientists were able to restore neurotransmission in the mice, thus rescuing cognition. While it is yet to be determined if LC plays a role in contextual learning in humans, scientists know that these neurons are affected in other neurodegenerative diseases, including Alzheimer's disease.
In addition, the team identified the gene fragment in mice that is largely responsible for LC degeneration – a region of about 32 genes including APP 23, 24. In a knockout mouse model with the third copy of APP deleted, the decrease in LC neurons did not occur, suggesting that App over-expression is necessary for LC degeneration. However, deleting the extra copy did not restore normal contextual learning behavior.
"Simply deleting the third App doesn't fix the behavior, so probably other gene products play a role in Down's syndrome," said Mobley. "However, giving the pro-drug to the mice rescued cognitive behaviors in a very dramatic way."
He noted that a form of this drug is currently in clinical trials to treat fibromyalgia in humans. "The possibility is very real that such a therapy, if proven safe, would be effective in treating dementia in later-stage Down's syndrome patients."
Additional contributors include Paul Aisen and Steven L. Wagner, UC San Diego Department of Neurosciences; and A. Salehi, M. Faizi, D. Colas, J. Valletta, J. Laguna, R. Takimoto-Kimura, A. Kleschevnikov and M. Shamloo, Stanford University.
The work was supported by the National Institutes of Health, the Larry L. Hillblom Foundation, the Down's Syndrome Research and Treatment Foundation, the Thrasher Research Fund, the Adler Foundation and the Alzheimer's Association.
Please visit http://neurosciences.ucsd.edu/ after 2 p.m. ET November 18 to view an interview with William Mobley and Steve Wagner of the UC San Diego Department of Neurosciences, discussing these findings.
Debra Kain | EurekAlert!
One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie
The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
20.04.2018 | Physics and Astronomy
20.04.2018 | Interdisciplinary Research
20.04.2018 | Physics and Astronomy