Alzheimer's, Down syndrome link found

By Bradley J. Fikes8:50 P.M.OCT. 26, 2014
1


Sanford-Burnham Medical Research Institute professor Dr. Huaxi Xu is a specialist in degenerative diseases. He is the senior author of a new study that shows how people with Down Syndrome invariably develop Alzheimer's Disease. — Peggy Peattie

A team at the Sanford-Burnham Medical Research Institute in La Jolla has reported an explanation for why people with Down syndrome often develop Alzheimer’s disease.

The study builds on research last year that suggested a cause for the mental disability that accompanies Down syndrome. If the continuing analysis results in new therapies, the syndrome could be alleviated and scientists might be able to harness that knowledge in treating — and perhaps even preventing — Alzheimer’s in the general population.

Such applications are years away because the study involves basic research, said Huaxi Xu, a Sanford-Burnham researcher who is senior author of the new paper, published Thursday in the journal Cell Reports. Xu and his colleagues — including Xin Wang, co-author of the latest report — are trying to translate the research into possible experimental drugs.

The common thread in both conditions is SNX27, a brain protein involved in complex molecular pathways that are still being scrutinized.

Down syndrome occurs when a child inherits a third copy of the 21st chromosome. Normally, one copy is inherited from each parent.

The abnormality, called trisomy, produces mild to moderate mental disability, a small head, upward slanting eyes, poor muscle tone and a single deep crease across the palm of the hand.

Last year’s study found that the brains of people with Down syndrome had abnormally low levels of SNX27, determined in post-mortem examinations. The third copy of the 21st chromosome includes a DNA segment that codes for a RNA molecule called miRNA-155. Production of this molecule reduces levels of SNX27, illustrating at the molecular level how trisomy impairs mental functioning.

Researchers also studied mice given a trisomy similar to humans with Down syndrome. These mice also became learning-deficient, as demonstrated by tests. And mouse neurons had fewer molecules called glutamate receptors, which are important for learning.

Some of the mice were treated with gene therapy that delivered a human version of the gene that makes SNX27. Those mice made more of the protein and they performed normally on learning tests. They were treated up to the age of 1 month, roughly at the equivalent stage of development for a 10-year-old human child.

It’s encouraging news to researchers who are working to produce a functional cure for those with Down syndrome, allowing them to live normal lives.

Toward that end, Xu and his teammates are working to find molecules that can increase production of SNX27.

ALZHEIMER’S CONNECTION

The new study discovered that SNX27 also regulates levels of beta amyloid plaques — tangled masses of protein that damage brain cells, causing them to die. The plaques have long been linked to Alzheimer’s in the general population.

Nearly all people with Down syndrome develop the characteristic beta amyloid plaques by age 40. Most of those individuals will develop Alzheimer’s symptoms — 25 percent of them by age 35 and 75 percent of them by age 65.

Xu’s team found that miRNA-155 suppresses production of SNX27 by adding another link to the complex chain of molecular events. Because SNX27 regulates production of beta amyloids, reducing it in turn lowers levels of beta amyloids.

There’s no conclusive proof that beta amyloid causes Alzheimer’s. In fact, a number of clinical trials aimed at treating the disease by reducing beta amyloid production have failed or shown extremely modest results.

But the evidence that beta amyloid damages neurons is so strong — and the correlation with Alzheimer’s so consistent — that Alzheimer’s researchers such as Dr. Paul Aisen at UC San Diego said it’s likely that potential therapies were previously given too late in the disease process, when symptoms already appeared.

SOCIETAL DEBATE

In the United States, about eight out of every 10,000 babies are born with Down syndrome. Their life expectancy has grown 456 percent between 1960 to 2007, according to the U.S. Centers for Disease Control and Prevention.

That greater longevity, the result of advancements in medical care, means far more people with the syndrome are living long enough to develop Alzheimer’s. So might this double health challenge prompt more parents to rethink their family plans if a diagnosis of Down syndrome arises?

Testing for the syndrome is becoming easier and safer with modern technology.

The traditional test required getting samples of fetal DNA through amniocentesis, which takes a small amount of fluid from the sac around the baby in the uterus. The procedure carries a risk of miscarriage.

Newer tests examine fetal DNA taken from the mother’s blood. The San Diego-based company Sequenom offers the MaterniT21 Plus test, which scans for Down syndrome and other trisomies and genetic abnormalities. Testing involves virtually no risk to the baby or mother.

Many couples opt for an abortion when they learn during the prenatal phase that their unborn child has the syndrome.

The topic is a source of enduring controversy.

“Abort (the fetus) and try again,” Richard Dawkins, the evolutionary biologist and outspoken atheist, said via Twitter on Aug. 20 to a woman who asked about the issue. “It would be immoral to bring it into the world if you have the choice.”
His remarks drew a firestorm of criticism in various forms.

Sarah Palin, mother of a son with Down syndrome, took to her Facebook page to invite Dawkins to meet that child, Trig.

“I’d let you meet my son if you promised to open your mind, your eyes and your heart to a unique kind of absolute beauty,” she wrote.

Dawkins then apologized on his website for the perception that his tweet was “rather heartless and callous,” blaming Twitter’s inherent brevity.

http://www.utsandiego.com/news/2014/oct/26/downs-syndrome-alzheimers-genes-research-biotech/