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A fix for Down syndrome brains?
Posted by Victoria Stern
[Entry posted at 18th November 2009 08:03 PM GMT]

Boosting levels of a neurotransmitter in the brain may reverse some of the cognitive abnormalities that characterize Down syndrome, according to a study, published online today (November 18) in Science Translational Medicine, conducted in a mouse model of the disease.

Child with Down syndrome
Image: Wikipedia
"The work is really fascinating," said Roger Reeves, a physiologist at Johns Hopkins Medical Institute who studies Down syndrome and was not involved in the research. "The study shows how to take the data from both human and animal model systems and turn them into potential molecules that can be used for therapy."

Down syndrome, a genetic disorder triggered by a third copy of human chromosome 21, is the most common cause of mental retardation in children and leads to deficits in contextual learning and memory. To study the neurological basis for these deficits, Ahmad Salehi and his colleagues at Stanford University School of Medicine turned to a well-established mouse model of the condition, in which mice are engineered to have an extra, third copy of 104 genes on chromosome 16 that are homologous to genes on human chromosome 21.

Mice with such a trisomy are known to show abnormal responses in behavioral tests for contextual learning. They don't respond to fear conditioning, for example -- suggesting they can't learn to associate a shock with a tone. Also, when provided with material with which to build nests, they use much less of it than normal mice and create shabbier homes, again reflecting their decreased ability to respond to new contexts.

The researchers first examined the brains of the mutant mice, and found a significant neurodegeneration in the locus coeruleus (LC), a brain area which produces and supplies other parts of the brain, including the hippocampus, with the neurotransmitter norepinephrine, essential for learning and memory function. That finding matched with the fact that the LC also degenerates in humans with Down syndrome.

"Contextual learning is an indicator of hippocampal function overall," said Reeves. "Finding a way to improve the function of the hippocampus is exactly where we want to go in Down syndrome research."

Since the locus coeruleus produces norepinephrine, the researchers then set out to determine how that neurotransmitter comes into play. When they injected the trisomy mice with l-DOPS, a drug that can cross the blood-brain barrier and convert into norepinephrine, the mice significantly improved their performance in tests of both fear conditioning and nest-building, behaving more like the normal animals. When the drug wore off, so too did the mutants' improved nest-building ability.

"The drug [l-DOPS] was able to restore contextual learning in the mouse model," Salehi said. "Treating [Down syndrome] with norepinephrine could be a new strategy to help improve the condition."

"Even in presence of degeneration the authors showed you can still rescue the function in the brain," said Lynn Nadel, a psychologist at the University of Arizona who studies Down syndrome and was not involved in this study. "Hopefully, this can lead to some sorts of early life interventions in humans."

The LC degeneration the researchers saw in the trisomy mice doesn't just affect humans with Down syndrome -- it is also seen in individuals with Alzheimer's disease and other types of dementia. Also, as many as 25% or more people with Down syndrome go on to develop Alzheimer's-type dementia -- a prevalence estimated to be three to five times greater than that of the general population. This link may arise via the gene App on chromosome 21, which codes for the amyloid precursor protein. This protein can form the amyloid plaques associated with early onset Alzheimer's. In some cases of Down syndrome but not others, App is present in three copies.

That's also true in the model mice, so to explore the relationship between the two diseases, Salehi and his colleagues compared the structure of the LC in trisomy mice with two versus three copies of App. Those with just two copies, they found, had a greater number of neurons producing norepinephrine.

"These results suggest that it may be possible to restore some cognitive function in Alzheimer's patients as well as Down syndrome sufferers using norepinephrine," said Salehi.

Nadel said that the "trick moving forward is to see how to go from this mouse model to a clinical trial in humans."

Reeves pointed out, however, that even before looking into human clinical trials, future studies will need to explore the optimum drug that can enhance the production of norepinephrine.

Related stories:
  • Alzheimer's clue found
    [29th July 2009]
  • A disease cell line library
    [7th August 2008]
  • Down syndrome traced to one gene
    [6th July 2006]

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    Rate this article

    Rating: 4.68/5 (25 votes )

    Carried away
    by anonymous poster

    [Comment posted 2009-12-15 08:55:24]
    You guys are getting carried away here with reactions to the work. If someone has a heart condition and can't function, it is totally acceptable for them to recieve treatment. In this case, no matter how wonderful they are, people with Down's have a brain condition and can't function in certain ways. So, finding a treatment that helps them function is beyond any idea of political correctness or judgement. If it anything, it give them and us more time and freedom to enjoy their uniqueness.

    by Adam Smith

    [Comment posted 2009-11-23 15:42:25]
    "Scientifically, anything mentally significantly less than the norm is a deficit, pure and simple."

    What an absurd comment. 'Scientifically' based on what? And who are you to say what is a strength and what is a weakness? Just because you believe that the strengths are minor doesn't necessarily make it so. What is scientifically true that is those with Trisomy 13 are different. The are not "mentally significantly less" because that would require a mental normal, itself an absurd concept.

    This is not "overzealous political correctness", this is respecting people for who they are and valuing differences, not try to make everyone the same. Just because you feel that these people are less than you, that they are "defects", please don't try to hide your prejudices in scientific terminology, your perverting the process.

    Bioethical "Correctness"
    by anonymous poster

    [Comment posted 2009-11-20 18:11:09]
    I personally find Tom Koch's comment disturbing. Scientifically, anything mentally significantly less than the norm is a deficit, pure and simple. To say it isn't by calling it something else or to magnify extremely minor "strengths" could detrimentally weaken the funding of treatments and scientific understanding of the processes.

    Overzealous political correctness has stifled open dialogue to the point that basic problems cannot be addressed. I would hate to see bioethical correctness stifle science and medicine.

    Great News

    [Comment posted 2009-11-19 13:17:21]
    I would welcome this type of research, I would do anything that made sense to help my daughter (2) have a happy and fulfilling life


    Down syndrome
    by TOM KOCH

    [Comment posted 2009-11-19 08:45:19]
    Victor Stern's 18 Nov. posting on "A Fix for Down Syndrome Brains" is disturbing. In it he refers persistently to a "disorder" with "deficits" that should be corrected.

    The Canadian Down syndrome Society defines Trisomy 21 as a naturally occurring genetic presence within the human community. Its members are, or can be, valuable contributors to their families and the community at large.

    The "deficits" are balanced by unusual strengths. In recent years we have learned that Trisomy 21 is cardio-protective, virtually illiminating conditions leading to heart attacks. The profile also is largely protective against breast cancer in women with Down syndrome.

    More importantly, however, persons with Down syndrome have strong emotional attributes and, typically, a perceptive intelligence that while it does not rank high on Stanford Binet scores is, we believe, is a real and important asset.

    This is not to argue against research like that Stern describes but it is to caution against easy and reflexive prejudices about a condition that is far more than a genetic profile. With the work Stern describes we equally need work to diminish prejudicial profiles of differences and promote social programs that maximize the potential of us all.

    Tom Koch, PhD
    bioethicist, Canadian Down syndrome Society (Resource Council).

    Comment on this news story

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