New Molecular Target is Key to Enhanced Brain Plasticity

As Alzheimer’s disease progresses, it kills brain cells mainly in the hippocampus and cortex, leading to impairments in “neuroplasticity,” the mechanism that affects learning, memory, and thinking. Targeting these areas of the brain, scientists hope to stop or slow the decline in brain plasticity, providing a novel way to treat Alzheimer’s. Groundbreaking new research has discovered a new way to preserve the flexibility and resilience of the brain.

The study, led by Tel Aviv University’s Prof. Illana Gozes and published in Molecular Psychiatry, reveals a nerve cell protective molecular target that is essential for brain plasticity. According to Prof. Gozes, “This discovery offers the world a new target for drug design and an understanding of mechanisms of cognitive enhancement.”

Prof. Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of TAU’s Sagol School of Neuroscience. Also contributing to the study were Dr. Saar Oz, Oxana Kapitansky, Yanina Ivashco-Pachima, Anna Malishkevich, Dr. Joel Hirsch, Dr. Rina Rosin-Arbersfeld, and their students, all from TAU. TAU staff scientists Dr. Eliezer Gildai and Dr. Leonid Mittelman provided the state-of-the-art molecular cloning and cellular protein imaging necessary for the study.

Building on past breakthroughs

The new finding is based on Prof. Gozes’ discovery of NAP, a snippet of a protein essential for brain formation (activity-dependent neuroprotective protein [ADNP]). As a result of this discovery, a drug candidate that showed efficacy in mild cognitive impairment patients, a precursor to Alzheimer’s disease, is being developed. NAP protects the brain by stabilizing microtubules — tiny cellular cylinders that provide “railways and scaffolding systems” to move biological material within cells and provide a cellular skeleton. Microtubules are of particular importance to nerve cells, which have long processes and would otherwise collapse. In neurodegenerative diseases like Alzheimer’s, the microtubule network falls apart, hindering cellular communication and cognitive function.

"Clinical studies have shown that Davunetide (NAP) protects memory in patients suffering from mild cognitive impairment preceding Alzheimer’s disease," said Prof. Gozes. "While the mechanism was understood in broad terms, the precise molecular target remained a mystery for years. Now, in light of our new research, we know why and we know how to proceed."

Stabilizing microtubules

The breakthrough was the discovery of the mechanism promoting microtubule growth at the tips of the tubes (“rails”). The researchers found that the NAP structure allows it to bind to the tip of the growing microtubule, the emerging “railway,” through specific microtubule end-binding proteins, which adhere to microtubules a bit like locomotors to provide for growth and forward movement, while the other end of the microtubule may to be disintegrating. These growing tips enlist regulatory proteins that are essential for providing plasticity at the nerve cell connection points, the synapses.

"We have now revealed that ADNP through its NAP motif binds the microtubule end binding proteins and enhances nerve cell plasticity, providing for brain resilience. We then discovered that NAP further enhances ADNP microtubule binding," said Prof. Gozes.

Researchers hope their discovery will help move Davunetide (NAP) and related compounds into further clinical trials, increasing the potential of future clinical use. Prof. Gozes is continuing to investigate microtubule end-binding proteins to better understand their protective properties in the brain.

Brain structure could predict risky behavior

Some people avoid risks at all costs, while others will put their wealth, health, and safety at risk without a thought. Researchers at Yale School of Medicine have found that the volume of the parietal cortex in the brain could predict where people fall on the risk-taking spectrum.

Led by Ifat Levy, assistant professor in comparative medicine and neurobiology at Yale School of Medicine, the team found that those with larger volume in a particular part of the parietal cortex were willing to take more risks than those with less volume in this part of the brain. The findings are published in the Sept. 10 issue of the Journal of Neuroscience.

Although several cognitive and personality traits are reflected in brain structure, there has been little research linking brain structure to economic preferences. Levy and her colleagues sought to examine this question in their study.

Study participants included young adult men and women from the northeastern United States. Participants made a series of choices between monetary lotteries that varied in their degree of risk, and the research team conducted standard anatomical MRI brain scans. The results were first obtained in a group of 28 participants, and then confirmed in a second, independent, group of 33 participants.

“Based on our findings, we could, in principle, use millions of existing medical brains scans to assess risk attitudes in populations,” said Levy. “It could also help us explain differences in risk attitudes based in part on structural brain differences.”

Levy cautions that the results do not speak to causality. “We don’t know if structural changes lead to behavioral changes or vice-versa,” she said.

Levy and her team had previously shown that risk aversion increases as people age, and we scientists also know that the cortex thins substantially with age. “It could be that this thinning explains the behavioral changes; we are now testing that possibility,” said Levy, who also notes that more studies in wider populations are needed.

Don’t Underestimate Your Mind’s Eye

Take a look around, and what do you see? Much more than you think you do, thanks to your finely tuned mind’s eye, which processes images without your even knowing.

A University of Arizona study has found that objects in our visual field of which we are not consciously aware still may influence our decisions. The findings refute traditional ideas about visual perception and cognition, and they could shed light on why we sometimes make decisions — stepping into a street, choosing not to merge into a traffic lane — without really knowing why.

Laura Cacciamani, who recently earned her doctorate in psychology with a minor in neuroscience, has found supporting evidence. Cacciamani’s is the lead author on a co-authored study, published online in the journal Attention, Perception and Psychophysics, shows that the brain’s subconscious processing has an impact on behavior and decision-making.

This seems to make evolutionary sense, Cacciamani said. Early humans would have required keen awareness of their surroundings on a subliminal level in order to survive.

"Your brain is always monitoring for meaning in the world, to be aware of your general surroundings and potential predators," Cacciamani said. "You can be focused on a task, but your brain is assessing the meaning of everything around you – even objects that you’re not consciously perceiving."

The study builds on the findings of earlier research by Jay Sanguinetti, who also was a doctoral candidate in the UA Department of Psychology. Both studies go against conventional wisdom among vision scientists.

"According to the traditional view, the brain accesses the meaning – or the memory – of an object after you perceive it," Cacciamani said. "Against this view, we have now shown that the meaning of an object can be accessed before conscious perception.

"We’re showing that there’s more interplay between memory and perception than previously has been assumed," she said.

Cacciamani asked participants in her study to classify nouns that appeared on a computer screen as naming a natural object or artificial object by pressing one of two buttons labeled “natural” or “artificial.” For example, the word “leaf” indicates an object found in nature, while “anchor” indicates a man-made or artificial object.

But before each word appeared on the screen, the computer flashed a black silhouette that – unknown to participants – had portions of natural or artificial objects suggested along the white outside regions (called the “ground” regions) of the image. Participants were not told to look for anything in the silhouettes, and they were flashed so quickly – 50 milliseconds – that it would have been difficult to notice the objects in the ground regions even if someone knew what to look for. Participants never were aware that the silhouette’s grounds suggested recognizable objects.

Cacciamani measured how well study participants performed at categorizing the words as natural or artificial by recording speed and accuracy.

"We found that participants performed better on the natural/artificial word task when that word followed a silhouette whose ground contained an object of the same rather than a different category," Cacciamani said.

This indicates that the brain accessed the meaning of the objects in the silhouette’s grounds even though study participants didn’t know the objects were there, she said.

"Every day our visual systems are bombarded with more information than we can consciously be aware of," Cacciamani said. "We’re showing that your brain might still be accessing information without your conscious awareness, and that could influence your behavior."

Xenon gas protects the brain after head injury

Head injury is the leading cause of death and disability in people aged under 45 in developed countries, mostly resulting from falls and road accidents. The primary injury caused by the initial mechanical force is followed by a secondary injury which develops in the hours and days afterwards. This secondary injury is largely responsible for patients’ mental and physical disabilities, but there are currently no drug treatments that can be given after the accident to stop it from occurring.

Scientists at Imperial College London found that xenon, given within hours of the initial injury, limits brain damage and improves neurological outcomes in mice, both in the short term and long term. The findings, published in the journal Critical Care Medicine, could lead to clinical trials of xenon as a treatment for head injury in humans.

Although xenon is chemically inert, this does not mean it is biologically inactive. Xenon has been known to have general anaesthetic properties since the 1950s. Previous studies at Imperial have found that xenon can protect brain cells from mechanical injury in the lab, but this new study is the first time such an effect has been shown in live animals, a vital step before any new treatments can be tested in humans.

Mice were anaesthetised before having a controlled mechanical force applied to the brain. Some were then treated with xenon at different concentrations and at different times after injury.

Mice treated with xenon performed better in tests assessing their neurological deficits, such as movement and balance problems, in the days after injury and after one month. They also had less brain damage, even if treatment was delayed up to three hours after the injury.

Dr Robert Dickinson from the Department of Surgery and Cancer at Imperial College London, who led the study, said: “After a blow to the head, most of the damage to the brain doesn’t occur immediately but in the hours and days afterwards. At present we have no specific drugs to limit the spread of the secondary injury, but we think that is the key to successful treatment.

“This study shows that xenon can prevent brain damage and disability in mice, and crucially it’s effective when given up to at least three hours after the injury. It’s feasible that someone who hits their head in an accident could be treated in the hospital or in an ambulance in this timeframe.

“These findings provide crucial evidence to support doing clinical trials in humans.”

Brain injuries no match for sPIF treatment

Researchers at Yale School of Medicine and their colleagues have uncovered a new pathway to help treat perinatal brain injuries. This research could also lead to treatments for traumatic brain injuries and neurodegenerative disorders such as Alzheimer’s and Parkinson’s.

The findings are published in the Sept. 8 issue of Proceedings of the National Academy of Sciences.

The MicroRNA molecule let-7 is known to cause the death of neurons in the central nervous system. The research team found that a synthetic molecule derived from the embryo called PreImplantation Factor (sPIF) protects against neuronal death and brain injury by targeting let-7. 

“We would never have connected the dots between PIF and let-7 without prior knowledge and experience on let-7 and H19, a developmentally regulated gene that is highly expressed in the developing embryo,” said senior author Dr. Yingqun Huang, associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Using a rat perinatal brain injury model, Huang and the team found that sPIF rescued damaged neurons and reduced inflammation. The team performed a series of in vivo and in vitro experiments and found that sPIF helped to stop the production of let-7. “We showed that sPIF works by destabilizing the key microRNA processing protein called KH-type splicing regulatory protein,” said Huang.

Lead author Martin Mueller, who helped develop the rat perinatal brain injury model, was surprised at the consistency of the results from both the in vivo and in vitro studies. “Collectively, our findings suggest that sPIF mitigates brain damage through a novel pathway,” said Mueller. “We saw more cortical brain volume and more neurons restored in brain damaged animals receiving sPIF.”

“For the first time, we have clear indication to pursue a new line of investigation in the treatment of perinatal brain injury, and possibly traumatic brain injury,” said co-author Dr. Michael Paidas, professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine.

Paidas, who is also vice chair of obstetrics at Yale, has helped to identify PIF’s effects with co-author Eytan R. Barnea, founder of the Society for the Investigation of Early Pregnancy (SIEP) and chief scientific officer of BioIncept, LLC. Barnea discovered and characterized PIF and described key elements of its mode of action.

Based on this promising data, the FDA has awarded sPIF fast-track designation and allowed a phase 1 sPIF clinical trial to treat patients with autoimmune liver disease at the University of Miami.

Eating habits, body fat related to differences in brain chemistry

People who are obese may be more susceptible to environmental food cues than their lean counterparts due to differences in brain chemistry that make eating more habitual and less rewarding, according to a National Institutes of Health study published in Molecular Psychiatry.

Researchers at the NIH Clinical Center found that, when examining 43 men and women with varying amounts of body fat, obese participants tended to have greater dopamine activity in the habit-forming region of the brain than lean counterparts, and less activity in the region controlling reward. Those differences could potentially make the obese people more drawn to overeat in response to food triggers and simultaneously making food less rewarding to them. A chemical messenger in the brain, dopamine influences reward, motivation and habit formation.

"While we cannot say whether obesity is a cause or an effect of these patterns of dopamine activity, eating based on unconscious habits rather than conscious choices could make it harder to achieve and maintain a healthy weight, especially when appetizing food cues are practically everywhere," said Kevin D. Hall, Ph.D., lead author and a senior investigator at National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of NIH. "This means that triggers such as the smell of popcorn at a movie theater or a commercial for a favorite food may have a stronger pull for an obese person – and a stronger reaction from their brain chemistry – than for a lean person exposed to the same trigger."

Study participants followed the same eating, sleeping and activity schedule. Tendency to overeat in response to triggers in the environment was determined from a detailed questionnaire. Positron emission tomography (PET) scans evaluated the sites in the brain where dopamine was able to act.

According to the Centers for Disease Control and Prevention, more than one-third of U.S. adults are obese. Obesity-related conditions include heart disease, type 2 diabetes and certain types of cancer, some of the leading causes of preventable death.

"These findings point to the complexity of obesity and contribute to our understanding of how people with varying amounts of body fat process information about food," said NIDDK Director Griffin P. Rodgers, M.D. "Accounting for differences in brain activity and related behaviors has the potential to inform the design of effective weight-loss programs."

The study did not demonstrate cause and effect among habit formation, reward, dopamine activity, eating behavior and obesity. Future research will examine dopamine activity and eating behavior in people over time as they change their diets, physical activity, and their weight.