Mechanism Tying Obesity to Alzheimer

If heart disease and diabetes aren’t bad enough, now comes another reason to watch your weight. According to a study just released, packing on too many pounds can increase the risk of developing Alzheimer’s disease.

A team led by researchers at the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia and Edith Cowan University in Joondalup, Western Australia has shown that being extremely overweight or obese increases the likelihood of developing Alzheimer’s. They found a strong correlation between body mass index and high levels of beta-amyloid, the sticky protein substance that builds up in the Alzheimer’s brain and is thought to play a major role in destroying nerve cells and in cognitive and behavioral problems associated with the disease.

“We looked at the levels of beta-amyloid and found a relationship between obesity and circulating amyloid,” says Sam E. Gandy, M.D., Ph.D., director of the Farber Institute for Neurosciences. “That’s almost certainly why the risk for Alzheimer’s is increased,” says Dr. Gandy, who is also professor of neurology, and biochemistry and molecular biology at Jefferson Medical College of Thomas Jefferson University. “Heightened levels of amyloid in the blood vessels and the brain indicate the start of the Alzheimer’s process.” The scientists reported their findings this month in the Journal of Alzheimer’s Disease.

According to, Dr. Gandy, evidence has emerged over the last five years that many of the conditions that raise the risk for heart disease such as obesity, uncontrolled diabetes, hypertension and hypercholesterolemia also increase the risk for Alzheimer’s. Yet exactly how such factors made an individual more likely to develop Alzheimer’s remained a mystery.

Dr. Gandy, Ralph Martins, Ph.D., of Edith Cowan University and their colleagues measured body mass index and beta-amyloid levels in the blood. They also looked at several other factors associated with heart disease and diabetes, such as the inflammatory marker C-reactive protein, insulin, and high density lipoprotein in 18 healthy adults who were either extremely overweight or obese. They found a “statistically significant correlation” between body mass index and beta-amyloid.

“Ours is one of the first attempts to try to find out on both the pathological and the molecular levels how obesity was increasing the risk of Alzheimer’s,” says Dr. Gandy, who serves as chairman of the Alzheimer's Association’s Medical and Scientific Advisory Council.

One implication of these findings could be that by losing excess weight and maintaining normal body weight, an individual might reduce the risk of developing Alzheimer’s. However, this has not been proven, notes Dr. Gandy.

“What’s especially interesting about this is that several studies are showing that even medical conditions in midlife may predispose to Alzheimer’s later on,” he says. “The baby boomers today should pay attention to this. Their medical risk factors today will play a role 30 years later. Think about weight, cholesterol, blood pressure, which could affect you long-term. In terms of Alzheimer’s, another risk factor is maintaining an active mental lifestyle.”

The next step is to follow such patients over the long term to see how many do indeed develop Alzheimer’s. “We need to first develop a medicine that is effective in humans in lowering amyloid accumulation or generation,” says Dr. Gandy. “We have those now in mice and we are testing them in humans. If we can develop such a medicine, then the question will be, if we can lower amyloid, will that in fact prevent Alzheimer’s?”

Source:
Newswise

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Bioinformatics predicts immune response to vaccinia virus

The use of computers to advance human disease research – known as bioinformatics -- has received a major boost from researchers at the La Jolla Institute for Allergy & Immunology (LIAI), who have used it to successfully predict immune response to one of the most complex viruses known to man – the vaccinia virus, which is used in the smallpox vaccine. Immune responses, which are essentially how the body fights a disease-causing agent, are a crucial element of vaccine development.

"We are excited because this further validates the important role that bioinformatics can play in the development of diagnostic tools and ultimately vaccines," said Alessandro Sette, Ph.D., an internationally known vaccine expert and head of LIAI's Emerging Infectious Disease and Biodefense Center. "We've shown that it can successfully reveal – with a very high degree of accuracy -- the vast majority of the epitopes (targets) that would trigger an effective immune response against a complex pathogen."

Bioinformatics holds significant interest in the scientific community because of its potential to move scientific research forward more quickly and at less expense than traditional laboratory testing.

The findings were published in a paper, "A consensus epitope prediction approach identifies the breadth of murine TCD8+-cell responses to vaccinia virus," in the online version of the journal Nature Biotechnology. LIAI scientist Magdalini Moutaftsi was the lead author on the paper.

While bioinformatics – which uses computer databases, algorithms and statistical techniques to analyze biological information -- is already in use as a predictor of immune response, the LIAI research team's findings were significant because they demonstrated an extremely high rate of prediction accuracy (95 percent) in a very complex pathogen – the vaccinia virus. The vaccinia virus is a non-dangerous virus used in the smallpox vaccine because it is related to the variola virus, which is the agent of smallpox. The scientific team was able to prove the accuracy of their computer results through animal testing.

"Before, we knew that the prediction methods we were using were working, but this study proves that they work very well with a high degree of accuracy," Sette said.

The researchers focused their testing on the Major Histocompatibility Complex (MHC), which binds to certain epitopes and is key to triggering the immune system to attack a virus-infected cell. Epitopes are pieces of a virus that the body's immune system focuses on when it begins an immune response. By understanding which epitopes will bind to the MHC molecule and cause an immune attack, scientists can use those epitopes to develop a vaccine to ward off illness – in this case to smallpox.

The scientists were able to find 95 percent of the MHC binding epitopes through the computer modeling. "This is the first time that bioinformatics prediction for epitope MHC binding can account for almost all of the (targeted) epitopes that are existing in very complex pathogens like vaccinia," said LIAI researcher Magdalini Moutaftsi. The LIAI scientists theorize that the bioinformatics prediction approach for epitope MHC binding will be applicable to other viruses.

"The beauty of the virus used for this study is that it's one of the most complex, large viruses that exist," said Moutaftsi. "If we can predict almost all (targeted) epitopes from such a large virus, then we should be able to do that very easily for less complex viruses like influenza, herpes or even HIV, and eventually apply this methodology to larger microbes such as tuberculosis."

The big advantage of using bioinformatics to predict immune system targets, explained Sette, is that it overcomes the need to manufacture and test large numbers of peptides in the laboratory to find which ones will initiate an immune response. Peptides are amino acid pieces that potentially can be recognized by the immune system. "There are literally thousands of peptides," explained Sette. "You might have to create and test hundreds or even thousands of them to find the right ones," he said. "With bioinformatics, the computer does the screening based on very complex mathematical algorithms. And it can do it in much less time and at much less expense than doing the testing in the lab."

The LIAI scientific team verified the accuracy of their computer findings by comparing the results against laboratory testing of the peptides and whole infectious virus in mice. "We studied the total response directed against infected cells," Sette said. "We compared it to the response against the 50 epitopes that had been predicted by the computer. We were pleased to see that our prediction could account for 95% of the total response directed against the virus."

Sources:
La Jolla Institute for Allergy and Immunology
Science Daily

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Stem cell superpowers exposed

Conversion factor for adult cells could sidestep cloning controversy.
Biologists say they are close to finding a cellular elixir of youth: a cocktail of proteins that can convert adult cells into embryonic stem cells that are able to grow replacement tissues.

Two studies published in Nature1,2 identify key proteins that endow embryonic stem cells with their coveted abilities to divide again and again, ad infinitum, and to generate all the different tissues in the body.

The papers do not provide a definitive recipe for the sought-after cocktail; either more proteins must be identified or those already known must be mixed in an unknown combination. But if found, this recipe could leapfrog the intense controversy and toil that is currently involved in extracting stem cells from a human embryo, which is destroyed in the process.

Instead, doctors might be able to take a simple biopsy of cells from a patient and reprogramme them, using one set of proteins to first transform them into embryonic stem cells, and then another to coax them into growing new blood, pancreas or other tissue.

"Until a couple of years ago I thought the idea of reprogramming was ridiculous because we had no scientific idea of how to achieve it," says stem cell biologist Austin Smith of Edinburgh University, UK. But now, he says, "it looks really encouraging. We could find a way to do this."

Bye bye, Dolly

When Dolly the sheep was unveiled in 1997, she was living evidence that the DNA in an adult nucleus can be reprogrammed by inserting it into an egg whose own nucleus has been removed. Somehow, the contents of the egg erased the genetic programme stamped on the DNA and established a new programme that could direct the growth of an embryo.

Since then, biologists have been searching for the proteins that drive reprogramming. They now know that cells can also be reprogrammed when they fuse with an embryonic stem (ES) cell. It seems there is something special in both eggs and ES cells that is transferred into adult cells and changes their behaviour.

Smith and his colleagues now show that a central element is a protein called Nanog, which controls other genes and is switched on in tiny growing embryos. They manufactured mouse embryonic stem cells that make four times more Nanog than usual. When fused with cells from the mouse nervous system, the hybrid cells were transformed into ES cells up to 200 times more efficiently than normal. "The result is just spectacular," Smith says.

It shows that Nanog is vital in driving other cells to become ES cells; but Smith says that injecting Nanog alone is not enough. Some other proteins are probably transferred during fusion as well.

A team led by Ihor Lemischka of Princeton University, New Jersey, has developed a way to identify some of these other players. They first screened through most of the known mouse genes for ones that were switched off when embryonic stem cells are transformed into other types of cell. Of the 70 genes they identified, the team then switched off each one individually in embryonic stem cells and examined whether they became other cell types.

Their search threw up Nanog plus a handful of other proteins that each seem to prevent embryonic stem cells from becoming particular tissues. The researchers suspect that some of these proteins, and maybe others, probably work together to reprogramme an adult cell.

The challenge now is to identify those other proteins and how they interact in order to complete the elusive recipe. Lemischka says he has already scaled-up his methods to search out some of these players. "Obviously that's where the field is really headed," he says. "It's a terribly exciting time."

Sources:
Ivanonva N., et al. Nature, doi:10.1038/nature04915 (2006).
Silva J., et al. Nature, doi:10.1038/nature04914 (2006).
news@nature.com

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