People With Down Syndrome Are Pioneers In Alzheimer's Research

by Jon Hamilton from NPR:
When researchers at the University of California, San Diego wanted to study an experimental Alzheimer's drug last year, they sought help from an unlikely group: people with Down syndrome.
"I had a CAT scan on my head, and I was in a special machine. It's called an MRI," says Justin McCowan, 39, whose parents drove him 125 miles from Santa Monica so he could participate in the study. McCowan also took brain function tests and spent hours with a needle in his arm so researchers could monitor levels of certain chemicals in his blood.
Alzheimer's researchers are increasingly interested in people like McCowan because "people with Down syndrome represent the world's largest population of individuals predisposed to getting Alzheimer's disease," says Michael Rafii, director of the Memory Disorders Clinic at UCSD.
Down syndrome is a genetic disorder that's best known for causing intellectual disability. But it also causes Alzheimer's. "By the age of 40, 100 percent of all individuals with Down syndrome have the pathology of Alzheimer's in their brain," Rafii says.
Down syndrome is caused by the presence of an extra copy of chromosome 21. And one of the genes on chromosome 21 happens to control the production of amyloid, the substance that forms the sticky plaques associated with Alzheimer's.
Because their bodies produce extra amyloid, most people with Down syndrome develop problems with thinking and memory by the time they reach 60. Rafii has chronicled the decline of one of his patients, a woman named Irma, by collecting her signatures from medical forms over the years.
The first one is from 1999, when Irma was in her mid-50s. "You can see her signature is on the line, it's clear, she wrote it in script," Rafii says. By 2005, though, she has switched to large block letters. By 2009, Irma is misspelling her name. By 2011, "there are only a few characters written that resemble letters," Rafii says. "And in the very last year it's completely blank."
People like Irma used to be rare because the medical problems associated with Down syndrome meant they rarely lived long enough to get dementia. Today, though, better medical treatments mean people with the disorder often live into their 60s.
And that has created a huge opportunity for Alzheimer's research, says William Mobley, chairman of the neuroscience department at UCSD. "This is the one group in the world that you could argue would benefit most by the institution of early therapy," he says.
Early therapy means starting people on drug treatment years before the symptoms of Alzheimer's appear. The approach has been hard to test because, in the general population, there's no good way to know who is going to develop Alzheimer's. But for people with Down syndrome, it's a near certainty.
Finding a drug that prevents Alzheimer's in people with Down syndrome could help millions of people who don't have the disorder, Mobley says. "This approach to treating Alzheimer's disease might apply to all of us," he says. "Imagine someday a drug that we all start taking when we're 25 so we never get Alzheimer's disease."
That's a long-term goal. But already, people with Down syndrome are making a difference in Alzheimer's research. Early work with Down patients helped confirm the importance of amyloid. More recently, people with the disorder helped test an eye exam that may offer a simple way to screen for Alzheimer's.
And then there's the study that Justin McCowan signed up for. It involves a drug from Transition Therapeutics called ELND005 that, in mice, can prevent the brain changes associated with Alzheimer's. Scientists hope the drug can do the same thing in people, including those with Down syndrome.
McCowan says he volunteered for the study because he wants to help other people, especially a friend of his named Maria, who also has Down syndrome. "I feel very sad about Maria because she doesn't remember anything," McCowan says.
His parents, Don and Annamarie McCowan, say their son's memory is still sharp. They hope that what scientists are learning from people like Justin will keep it that way.

How Down syndrome may help unravel Alzheimer's puzzle

by Linda Carroll from NBC NEWS Today:
Scientists have known for decades that people with Down syndrome were at increased risk of developing Alzheimer’s disease, but they didn’t know why. Some researchers now believe that understanding the connection between the two conditions might help us unravel the Alzheimer’s puzzle and point towards therapies that might slow, or even halt, the dreaded disease.

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“It’s a tantalizing and provocative question: Do people with Down syndrome hold the key to the mystery of Alzheimer’s development?” Dr. Brian Skotko, co-director of the Down Syndrome Program at the Massachusetts General Hospital in Boston, said in a telephone interview. “And what can we learn from those with Down syndrome that will benefit the rest of the population?”

Down Syndrome Treatment Study Shows Experimental Drug Reverses Cognitive Deficits In Mice

 by David Freeman from the Huffington Post:
There's still no cure for Down syndrome, but recent research is raising hopes that drugs can be found to counter the cognitive deficit that characterizes the genetic disorder.
In July, University of Massachusetts researchers said they had found a way to shut down the extra chromosome that causes the syndrome, at least in test tubes. And now comes word that scientists have identified a compound that brings dramatic improvements in learning and memory in mice bred to have a Down-like condition. One injection of the compound given on the day of birth seemed to work by allowing the animals' cerebellums to grow to full size.
"Most people with Down syndrome have a cerebellum that's about 60 percent of the normal size," Dr. Roger H. Reeves, a professor at Johns Hopkins University and one of the scientists behind the research, said in a written statement. "We treated the Down syndrome-like mice with a compound we thought might normalize the cerebellum's growth, and it worked beautifully... We were able to completely normalize growth of the cerebellum through adulthood with that single injection."

Molecular Roots of Down Syndrome Unraveled

Neurons from a typical mouse (left) are longer and fuller than neurons from a mouse lacking SNX27 (right). (Credit: Image courtesy of Sanford-Burnham Medical Research Institute)

from Science Daily:
Researchers have discovered that the extra chromosome inherited in Down syndrome impairs learning and memory because it leads to low levels of SNX27 protein in the brain.
What is it about the extra chromosome inherited in Down syndrome -- chromosome 21 -- that alters brain and body development? Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have new evidence that points to a protein called sorting nexin 27, or SNX27. SNX27 production is inhibited by a molecule encoded on chromosome 21. The study, published March 24 in Nature Medicine, shows that SNX27 is reduced in human Down syndrome brains. The extra copy of chromosome 21 means a person with Down syndrome produces less SNX27 protein, which in turn disrupts brain function. What's more, the researchers showed that restoring SNX27 in Down syndrome mice improves cognitive function and behavior.
"In the brain, SNX27 keeps certain receptors on the cell surface -- receptors that are necessary for neurons to fire properly," said Huaxi Xu, Ph.D., professor in Sanford-Burnham's Del E. Webb Neuroscience, Aging and Stem Cell Research Center and senior author of the study. "So, in Down syndrome, we believe lack of SNX27 is at least partly to blame for developmental and cognitive defects."

SNX27's role in brain function
Xu and colleagues started out working with mice that lack one copy of the snx27 gene. They noticed that the mice were mostly normal, but showed some significant defects in learning and memory. So the team dug deeper to determine why SNX27 would have that effect. They found that SNX27 helps keep glutamate receptors on the cell surface in neurons. Neurons need glutamate receptors in order to function correctly. With less SNX27, these mice had fewer active glutamate receptors and thus impaired learning and memory.

Lithium restores cognitive function in Down syndrome trial

by Paul Hamaker from the Examiner.com:
Researchers led by Laura Gasparini at the Istituto Italiano di Tecnologia in Genova Italy are the first to report the restoration of cognitive functions in Down syndrome mice using lithium in the December 3, 2012, issue of the Journal of Clinical Investigation.
Lithium has been shown to be useful in the treatment of several mood disorders in humans and is particularly affective in the treatment of bipolar disorder.
Mice are used in human brain disease studies because mouse brain chemistry is very close to human brain chemistry.
The Down syndrome mice were tested in tasks measuring contextual learning, spatial memory, and object discrimination before and after being treated with lithium. The mice demonstrated a marked improvement in memory function after treatment with lithium.
Remarkably the Down syndrome mice also showed restored neurogenesis (regrowth and rebirth of nerve cells) in the hippocampus. The hippocampus is directly associated with learning and memory.
Not ready for humans yet, this first success implies a significant improvement in the treatment of Down syndrome using a drug that is known to be safe for most people.
The most recent statistics from the Centers for Disease Control and Prevention that considered cases of Down syndrome in Alabama indicate an increased number of Down syndrome births by 8.4 percent. No defined cause has been found for the increase.
The research was reviewed at the Eureka Alert website the date of publication.

Prenatal intervention reduces learning deficit in mice

from Science Codex:
Mice with a condition that serves as a laboratory model for Down syndrome perform better on memory and learning tasks as adults if they were treated before birth with neuroprotective peptides, according to researchers at the National Institutes of Health.
Down syndrome results when an individual receives an extra copy of chromosome 21. According to the Centers for Disease Control and Prevention, Down syndrome occurs in 1 of every 691 births. Features of Down syndrome include delays in mental and physical development and poor muscle tone. These features may vary greatly, ranging from mild to severe.
The researchers studied growth factors that are important at certain key stages of brain development in the womb. Named for the first three amino acids making up their chemical sequence, NAP and SAL, are small peptides (small protein sub units) of two proteins. These two proteins enhance the ability of brain cells to receive and transmit signals, and enable them to survive. (NAP is an abbreviation for NAPVSIPQ and SALfor SALLRSIPA.)
The mice in the study had an extra copy of mouse chromosome 16, which has mouse counterparts to 55 percent of the genes on human chromosome 21.The researchers treated pregnant mice with NAP and SAL for five days, then tested the mouse offspring at 8 to 12 months of age, comparing them to mice treated with a saline solution (placebo). Mice with the extra chromosomal material that were treated with NAP and SAL in the womb learned as well as mice that did not have the extra chromosome, and significantly faster than mice with the extra chromosome that were treated with saline solution.
"Our study has provided important information that may help in the understanding of Down syndrome," said senior author Catherine Y. Spong, M.D., chief of the unit on perinatal and developmental neurobiology at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute where the research was conducted.
Dr. Spong collaborated with first author Maddalena Incerti, M.D., Kari Horowitz MD, Robin Roberson, Daniel Abebe, Laura Toso, M.D., and Madeline Caballero, all of the NICHD Unit on Perinatal and Developmental Neurobiology. Dr. Incerti also is affiliated with the University of Milano-Bicocca, Italy, and Dr. Horowitz now is affiliated with the University of Connecticut, Farmington.
Their findings appear online in PLOS ONE.
In an earlier study, Dr. Spong and her colleagues found that, if treated with NAP and SAL in the womb, mice with the extra copy of chromosome 16, achieved developmental milestones earlier than did mice with an extra copy of chromosome 16 that had not been treated. In that study, the researchers examined developmental milestones for sensory, motor skill, and muscle tone development in the first three weeks of life.
"In our earlier work, we showed that treating the mice during pregnancy could prevent developmental delay as assessed with milestones," Dr. Spong said. "In this study, we showed that treatment with NAP and SAL not only puts the animals on a typical developmental trajectory, it also improves their ability to learn.
For the current study, pregnant mice received injections of the two protein fragments starting eight days after conception. This is equivalent to the end of the first trimester in a human pregnancy.
The researchers tested the learning skills of the mice when the animals reached adulthood. The mice were placed in a tank of water on a clear platform. The tank had symbols on each wall that the mice could use to orient themselves. Researchers then placed the mice directly in the water and timed how long it took them to locate the platform. With repeated trials, the mice become more adept at the task and take less time to reach the platform.
Over five days of testing, the researchers found that the time spent searching for the platform decreased substantially for all groups except the mice with the extra copy of chromosome 16 that were not treated with NAP and SAL in the womb.
The research of Dr. Spong's team is part of an NIH-wide focus on Down syndrome outlined in a 2007 Down syndrome research plan. The plan highlights research priorities for the field, including establishing a Down syndrome patient registry, which was announced Oct. 25, 2012.

Source: NIH/National Institute of Child Health and Human Development