Scientists at The Scripps Research Institute (TSRI) have unravelled one of the major toxic mechanisms of Alzheimer`s disease.

The discoveries could lead to a much better understanding of the Alzheimer`s process and how to prevent it.

The findings showed that brain damage in Alzheimer`s disease is linked to the overactivation of an enzyme called AMPK. When the scientists blocked this enzyme in mouse models of the disease, neurons were protected from loss of synapses-neuron-to-neuron connection points-typical of the early phase of Alzheimer`s disease.

In addition to having implications for Alzheimer`s drug discovery, TSRI Professor Franck Polleux, who led the new study, noted the findings suggest the need for further safety studies on an existing drug, metformin. Metformin, a popular treatment for Type 2 Diabetes, causes AMPK activation.

Georges Mairet-Coello, a postdoctoral research associate in the Polleux lab, performed most of the experiments for the new study.

He began by confirming that amyloid beta, in the small-aggregate ("oligomer") form that is toxic to synapses, does indeed strongly activate AMPK; amyloid beta oligomers stimulate certain neuronal receptors, which in turn causes an influx of calcium ions into the neurons.

He found that this calcium influx triggers the activation of an enzyme called CAMKK2, which appears to be the main activator of AMPK in neurons.

The team then showed that this AMPK overactivation in neurons is the essential reason for amyloid beta`s synapse-harming effect. Normally, the addition of amyloid beta oligomers to a culture of neurons causes the swift disappearance of many of the neurons` dendritic spines-the rootlike, synapse-bearing input stalks that receive signals from other neurons.

With a variety of tests on mice, the scientists showed that amyloid beta oligomers can`t cause this dendritic spine loss unless AMPK overactivation occurs-and indeed AMPK overactivation on its own can cause the spine loss.

Next Mairet-Coello investigated the role of the tau protein. Ordinarily it serves as a structural element in neuronal axons, but in Alzheimer`s it somehow becomes hyperphosphorylated and drifts into other neuronal areas, including dendrites where its presence is associated with spine loss.
Recent studies have shown that amyloid beta`s toxicity to dendritic spines depends largely on the presence of tau, but just how the two Alzheimer`s proteins interact has been unclear.

The team took a cue from a 2004 study of Drosophila fruit flies, in which an AMPK-like enzyme`s phosphorylation of specific sites on the tau protein led to a cascade of further phosphorylations and the degeneration of nerve cells. The scientists confirmed that one of these sites, S262, is indeed phosphorylated by AMPK.

They then showed that this specific phosphorylation of tau accounts to a significant extent for amyloid beta`s synapse toxicity.

"Blocking the phosphorylation at S262, by using a mutant form of tau that can`t be phosphorylated at that site, prevented amyloid beta`s toxic effect on spine density," Mairet-Coello said.

The result suggests that amyloid beta contributes to Alzheimer`s via AMPK, mostly as an enabler of tau`s toxicity.

The findings were recently reported in the journal Neuron.

A group of researchers from the University of Oxford believe they have engineered a protein from flesh-eating bacteria that acts as a molecular `superglue` and could be used to help detect cancer cells.

"We`ve turned the tables and put one kind of flesh-eating bacterium to good use," said Mark Howarth, Ph.D., who led the research.

"We have engineered one of its proteins into a molecular superglue that adheres so tightly that the set-up we used to measure the strength actually broke. It resists high and low temperatures, acids and other harsh conditions and seals quickly.

"With this material we can lock proteins together in ways that could underpin better diagnostic tests - for early detection of cancer cells circulating in the blood, for instance. There are many uses in research, such as probing how the forces inside cells change the biochemistry and affect health and disease."

Howarth`s team at the University of Oxford in the United Kingdom genetically engineered the glue from a protein, FbaB, that helps Streptococcus pyogenes (S. pyogenes) bacteria infect cells. S. pyogenes is one of the microbes that can cause the rare necrotizing fasciitis, or flesh-eating bacteria syndrome, in which difficult-to-treat infections destroy body tissue.

They split FbaB into two parts, a larger protein and a smaller protein subunit, termed a peptide. Abbreviating S. pyogenes as "Spy," they named the small peptide "SpyTag" and the larger protein "SpyCatcher."

The gluing action occurs when SpyTag and SpyCatcher meet. They quickly lock together by forming one of the strongest possible chemical bonds. SpyCatcher and SpyTag can be attached to the millions of proteins in the human body and other living things, thus gluing proteins together.

One of the applications on the horizon involves testing the technology as a new way to detect "circulating tumor cells," or CTCs. Tumors shed these cells into the bloodstream, where they may act as seeds, spreading or metastasizing cancer from the original site to other parts of the body.

That spreading is the reason why cancer is such a serious health problem.

Howarth said that the Spy technology has advantages over other molecular gluing systems that are available. SpyCatcher and SpyTag, for instance, can glue two proteins together at any point in the protein.
"That flexibility allows us many different ways to label proteins and gives us new approaches to assemble proteins together for diagnostic tests," Howarth explained.

The study was recently presented at the 245th National Meeting and Exposition of the American Chemical Society.

Teenagers who increased the days on which they got just 20 minutes of exercise, equivalent to a short walk, were able to cut down on their smoking habit, according to a study.

It also found teenage smokers were more likely to quit altogether if they participated in a smoking cessation/fitness program-and they ramped up the days on which they got at least 30 minutes of physical activity.

"This study adds to evidence suggesting that exercise can help teenagers who are trying to quit smoking," said lead author Kimberly Horn, EdD, the Associate Dean for Research at the George Washington University School of Public Health and Health Services (SPHHS).

"Teens who boosted the number of days on which they engaged in at least 20 minutes of exercise, equivalent to a short walk, were more likely than their peers to resist lighting up a cigarette," the researcher stated.

Horn and her colleagues tracked 233 teenagers from 19 high schools in West Virginia, a state with among the highest smoking rates in the nation. The participants in the study were daily smokers with other risky behaviors.

That study found that an intensive smoking cessation intervention combined with a fitness program was the most successful way to help teenagers quit.

In the current study, Horn`s team looked to see if an increase in physical activity would help teens quit regardless of the type of intervention. In this study, as in the previous one, some teenagers went through an intensive anti-smoking program combined with a fitness intervention while others just got the smoking cessation program and still others listened to a short anti-smoking lecture.

Horn found that all of the teens increased their exercise activity to some degree-just by virtue of being in the study. However, teens who reported increasing the number of days in which they got just 20 minutes a day of exercise were able to significantly cut back on the cigarettes they smoked.

Horn`s previous study showed that the most powerful way for teens to quit smoking was if they participated in a program called Not-On-Tobacco; it was even more powerful for boys with an added fitness component. The researchers believe that the 20-minute threshold for changing smoking behavior deserves further study.

But Horn noted that the study has limitations.

"We don`t fully understand the clinical relevance of ramping up daily activity to 20 or 30 minutes a day with these teens. But we do know that even modest improvements in exercise may have health benefits. Our study supports the idea that encouraging one healthy behavior can serve to promote another, and it shows that teens, often viewed as resistant to behavior change, can tackle two health behaviors at once," she added.

And researchers still do not know the mechanism that might explain the findings. However, she says that physical activity is known to spur the release of the body`s feel-good chemicals called endorphins.

One possible explanation is that those substances might help teen smokers better deal with the cravings or weather the withdrawal symptoms that often lead to relapse, she said.

The study appeared online in the Journal of Adolescent Health, the official publication of the Society for Adolescent Medicine.

Scientists have for the first time been able to predict how much pain people are feeling by looking at images of their brains.

The new study led by the University of Colorado Boulder may lead to the development of reliable methods doctors can use to objectively quantify a patient`s pain.

Currently, pain intensity can only be measured based on a patient`s own description, which often includes rating the pain on a scale of one to 10.

Objective measures of pain could confirm these pain reports and provide new clues into how the brain generates different types of pain.

The new research results also may set the stage for the development of methods using brain scans to objectively measure anxiety, depression, anger or other emotional states.

"Right now, there`s no clinically acceptable way to measure pain and other emotions other than to ask a person how they feel," Tor Wager, associate professor of psychology and neuroscience at CU-Boulder and lead author of the paper, said.

The research team, which included scientists from New York University, Johns Hopkins University and the University of Michigan, used computer data-mining techniques to comb through images of 114 brains that were taken when the subjects were exposed to multiple levels of heat, ranging from benignly warm to painfully hot.

With the help of the computer, the scientists identified a distinct neurologic signature for the pain.

"We found a pattern across multiple systems in the brain that is diagnostic of how much pain people feel in response to painful heat," Wager said.

Going into the study, the researchers expected that if a pain signature could be found it would likely be unique to each individual.

If that were the case, a person`s pain level could only be predicted based on past images of his or her own brain.

But instead, they found that the signature was transferable across different people, allowing the scientists to predict how much pain a person was being caused by the applied heat, with between 90 and 100 percent accuracy, even with no prior brain scans of that individual to use as a reference point.

The results of the study do not yet allow physicians to quantify physical pain, but they lay the foundation for future work that could produce the first objective tests of pain by doctors and hospitals.

To that end, Wager and his colleagues are already testing how the neurologic signature holds up when applied to different types of pain.

The findings are published in the New England Journal of Medicine.

Researchers have successfully implanted pacemaker electrodes into the brains of patients suffering from major depression, with symptoms of six out of seven of them improving considerably and rapidly.

Dr Volker Arnd Coenen, neurosurgeon at the Department of Neurosurgery at the Bonn University Hospital in Germany, implanted electrodes into the medial fore-brain bundles in the brains of subjects suffering from major depression with the electrodes being connected to a brain pacemaker.

The nerve cells were then stimulated by means of a weak electrical current, a method called Deep Brain Stimulation. In a matter of days, in six out of seven patients, symptoms such as anxiety, despondence, listlessness and joylessness had improved considerably.

"Such sensational success both in terms of the strength of the effects, as well as the speed of the response has so far not been achieved with any other method," said Dr Thomas E Schlapfer from the Bonn University Hospital Department of Psychiatry and Psychotherapy.

The medial fore-brain bundle is a bundle of nerve fibres running from the deep-seated limbic system to the prefrontal cortex. In a certain place, the bundle is particularly narrow because the individual nerve fibres lie close together.

"This is exactly the location in which we can have maximum effect using a minimum of current," Coenen said.

The medial fore-brain bundle is a central part of a euphoria circuit belonging to the brain`s reward system. What kind of effect stimulation exactly has on nerve cells is not yet known. But it obviously changes metabolic activity in the different brain centers.

The researchers have already shown in several studies that deep brain stimulation shows an amazing and - given the severity of the symptoms - unexpected degree of amelioration of symptoms in major depression.

In those studies, however, the physicians had not implanted the electrodes into the medial fore-brain bundle but instead into the nucleus accumbens, another part of the brain`s reward system. This had resulted in clear and sustainable improvements in about 50 per cent of subjects.

"But in this new study, our results were even much better," said Schlapfer in a statement.

A clear improvement in complaints was found in 85 per cent of patients, instead of the earlier 50 per cent. In addition, stimulation was performed with lower current levels, and the effects showed within a few days, instead of after weeks.

The study was published in the international journal Biological Psychiatry.