Scientists Identify Buphenyl as a Possible Drug for Alzheimer’s disease

Buphenyl, an FDA-approved medication for hyperammonemia, may protect memory and prevent the progression of Alzheimer’s disease. Hyperammonemia is a life-threatening condition that can affect patients at any age. It is caused by abnormal, high levels of ammonia in the blood.

Studies in mice with Alzheimer’s disease (AD) have shown that sodium phenylbutyrate, known as Buphenyl, successfully increases factors for neuronal growth and protects learning and memory, according to neurological researchers at the Rush University Medical Center.

Results from the National Institutes of Health funded study, recently were published in the Journal of Biological Chemistry.

“Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Alzheimer’s disease,” said Kalipada Pahan, PhD, the Floyd A. Davis professor of neurology at Rush and lead investigator of this study.

A family of proteins known as neurotrophic factors help in survival and function of neurons. Past research indicates that these proteins are drastically decreased in the brain of patients with Alzheimer’s disease (AD).

“Neurotrophic factor proteins could be increased in the brain by direct injection or gene delivery,” said Pahan. “However, using an oral medication to increase the level of these protein may be the best clinical option and a cost effective way to increase the level of these proteins directly in the brain.”

“Our study found that after oral feeding, Buphenyl enters into the brain, increases these beneficial proteins in the brain, protects neurons, and improves memory and learning in mice with AD-like pathology,” said Pahan.

In the brain of a patient with AD, two abnormal structures called plaques and tangles are prime suspects in damaging and killing nerve cells. While neurons die, other brain cells like astroglia do not die.

The study findings indicate that Buphenyl increases neurotrophic factors from astroglia. Buphenyl stimulates memory-related protein CREB (cyclic AMP response element-binding protein) using another protein known as Protein Kinase C (PKC) and increases neurotrophic factors in the brain.

"Now we need to translate this finding to the clinic and test Buphenyl in Alzheimer’s disease patients,” said Pahan. “If these results are replicated in Alzheimer’s disease patients, it would open up a promising avenue of treatment of this devastating neurodegenerative disease.”

Bees get a buzz from caffeine

You may need a cup of coffee to kick start the day but it seems honeybees also get their buzz from drinking flower nectar containing caffeine.

Publishing in Science, researchers have shown that caffeine improves a honeybee’s memory and could help the plant recruit more bees to spread its pollen.

In tests honeybees feeding on a sugar solution containing caffeine, which occurs naturally in the nectar of coffee and citrus flowers, were three times more likely to remember a flower’s scent than those feeding on just sugar.

Study leader Dr Geraldine Wright, Reader in Neuroethology at Newcastle University, explained that the effect of caffeine benefits both the honeybee and the plant: “Remembering floral traits is difficult for bees to perform at a fast pace as they fly from flower to flower and we have found that caffeine helps the bee remember where the flowers are.

“In turn, bees that have fed on caffeine-laced nectar are laden with coffee pollen and these bees search for other coffee plants to find more nectar, leading to better pollination.

“So, caffeine in nectar is likely to improve the bee’s foraging prowess while providing the plant with a more faithful pollinator.”

In the study, researchers found that the nectar of Citrus and Coffea species often contained low doses of caffeine. They included ‘robusta’ coffee species mainly used to produce freeze-dried coffee and ‘arabica’ used for espresso and filter coffee. Grapefruit, lemons, pomelo and oranges were also sampled and all contained caffeine.

Co-author Professor Phil Stevenson from the Royal Botanic Gardens, Kew and the University of Greenwich’s Natural Resources Institute said: “Caffeine is a defence chemical in plants and tastes bitter to many insects including bees so we were surprised to find it in the nectar.  However, it occurs at a dose that’s too low for the bees to taste but high enough to affect bee behaviour.”

The effect of caffeine on the bees’ long-term memory was profound with three times as many bees remembering the floral scent 24 hours later and twice as many bees remembering the scent after three days.

Typically, the nectar in the flower of a coffee plant contains almost as much caffeine as a cup of instant coffee. Just as black coffee has a strong bitter taste to us, high concentrations of caffeine are repellent to honeybees.

Dr Wright added: “This work helps us understand the basic mechanisms of how caffeine affects our brains. What we see in bees could explain why people prefer to drink coffee when studying.”

Dr Julie Mustard, a contributor to the study from Arizona State University, explains further: “Although human and honeybee brains obviously have lots of differences, when you look at the level of cells, proteins and genes, human and bee brains function very similarly. Thus, we can use the honeybee to investigate how caffeine affects our own brains and behaviours.”

This project was funded in part by the Insect Pollinators Initiative which supports projects aimed at researching the causes and consequences of threats to insect pollinators and to inform the development of appropriate mitigation strategies.

Population declines among bees have serious consequences for natural ecosystems and agriculture since bees are essential pollinators for many crops and wild flowering species. If declines are allowed to continue there is a risk to our natural biodiversity and on some crop production.

Professor Stevenson said: “Understanding how bees choose to forage and return to some flowers over others will help inform how landscapes could be better managed. Understanding a honeybee’s habits and preferences could help find ways to reinvigorate the species to protect our farming industry and countryside.”

Use It or Lose It

"Use it or lose it." The saying could apply especially to the brain when it comes to protecting against Alzheimer’s disease. Previous studies have shown that keeping the mind active, exercising and social interactions may help delay the onset of dementia in Alzheimer’s disease.

Now, a new study led by Dennis Selkoe, MD, co-director of the Center for Neurologic Diseases in the Brigham and Women’s Hospital (BWH) Department of Neurology, provides specific pre-clinical scientific evidence supporting the concept that prolonged and intensive stimulation by an enriched environment, especially regular exposure to new activities, may have beneficial effects in delaying one of the key negative factors in Alzheimer’s disease.

The study will be published online on March 6, 2013 in Neuron.

Alzheimer’s disease occurs when a protein called amyloid beta accumulates and forms “senile plaques” in the brain. This protein accumulation can block nerve cells in the brain from properly communicating with one another. This may gradually lead to an erosion of a person’s mental processes, such as memory, attention, and the ability to learn, understand and process information.

The BWH researchers used a wild-type mouse model when evaluating how the environment might affect Alzheimer’s disease. Unlike other pre-clinical models used in Alzheimer’s disease research, wild-type mice tend to more closely mimic the scenario of average humans developing the disease under normal environmental conditions, rather than being strongly genetically pre-disposed to the disease.

Selkoe and his team found that prolonged exposure to an enriched environment activated certain adrenalin-related brain receptors which triggered a signaling pathway that prevented amyloid beta protein from weakening the communication between nerve cells in the brain’s “memory center,” the hippocampus. The hippocampus plays an important role in both short- and long-term memory.

The ability of an enriched, novel environment to prevent amyloid beta protein from affecting the signaling strength and communication between nerve cells was seen in both young and middle-aged wild-type mice.

"This part of our work suggests that prolonged exposure to a richer, more novel environment beginning even in middle age might help protect the hippocampus from the bad effects of amyloid beta, which builds up to toxic levels in one hundred percent of Alzheimer patients," said Selkoe.

Moreover, the scientists found that exposing the brain to novel activities in particular provided greater protection against Alzheimer’s disease than did just aerobic exercise. According to the researchers, this observation may be due to stimulation that occurred not only physically, but also mentally, when the mice moved quickly from one novel object to another.

"This work helps provide a molecular mechanism for why a richer environment can help lessen the memory-eroding effects of the build-up of amyloid beta protein with age," said Selkoe. "They point to basic scientific reasons for the apparent lessening of AD risk in people with cognitively richer and more complex experiences during life."

Reconstructing the Past: How Recalling Memories Alters Them

Recently the neurologist and author Oliver Sacks recalled a vivid childhood memory, recounted in his autobiography, Uncle Tungsten.

During WWII he lived in London during the Blitz, and on one occasion:

"…an incendiary bomb, a thermite bomb, fell behind our house and burned with a terrible, white-hot heat. My father had a stirrup pump, and my brothers carried pails of water to him, but water seemed useless against this infernal fire—indeed, made it burn even more furiously. There was a vicious hissing and sputtering when the water hit the white-hot metal, and meanwhile the bomb was melting its own casing and throwing blobs and jets of molten metal in all directions."

Except when his autobiography came out, one of his older brothers told him he’d misremembered the event. In fact both of them had been at school when the bomb struck so they could not have witnessed the explosion.

The ‘false’ memory, it turned out, was implanted by a letter. Their elder brother had written to them, describing the frightening event, and this had lodged in his mind. Over the years the letter had gone from a third-person report to a first-person ‘memory’.

Turning the memory over in his mind, Sacks writes that he still cannot see how the memory of the bomb exploding can be false. There is no difference between this memory and others he knows to be true; it felt like he was really there.

This sort of experience is probably much more common than we might like to imagine. Many memories which have the scent of authenticity may turn out to be misremembered, if not totally fictitious events, if only we could check. Without some other source with which to corroborate, it is hard verify the facts, especially for events that took place long ago.

That these sorts of distortions to memory happen is unquestioned, what fascinates is how it comes about. Does the long passage of time warp the memory, or is there some more active process that causes the change?

A study published recently sheds some light on this process and provides a model for how memories like Sack’s become distorted.

Changes in patterns of brain activity predict fear memory formation

Psychologists at the University of Amsterdam (UvA) have discovered that changes in patterns of brain activity during fearful experiences predict whether a long-term fear memory is formed. The research results have recently been published in the prestigious scientific journal ‘Nature Neuroscience’.

Researchers Renee Visser MSc, Dr Steven Scholte, Tinka Beemsterboer MSc and Prof. Merel Kindt discovered that they can predict future fear memories by looking at patterns of brain activity during fearful experiences. Up until now, there was no way of predicting fear memory. It was also, above all, unclear whether the selection of information to be stored in the long-term memory occurred at the time of fear learning or after the event.

Picture predicts pain stimulus

During magnetic resonance brain imaging (MRI), participants saw neutral pictures of faces and houses, some of which were followed by a small electric shock. In this way, the participants formed fear memories. They showed fear responses when the pictures were shown that were paired with shocks. This fear response can be measured in the brain, but is also evident from increased pupil dilation when someone sees the picture. After a few weeks, the participants returned to the lab and were shown the same images. Brain activity and pupil diameter were once again measured. The extent to which the pupil dilated when seeing the images that were previously followed by a shock, was considered an expression of the previously formed fear memory.

Pattern Analysis

In order to analyse the fMRI data, (spatial) patterns of brain activity (Multi-Voxel Pattern Analysis, or MVPA) were analysed. By correlating patterns of various stimulus presentations with each other, it is possible to measure the extent to which the representation of two stimuli is the same. It appears that images that have nothing in common, such as houses and faces, lead to increasing neural pattern similarity when they predict danger. This does not occur when they do not predict danger. This leads to the formation of stronger fear responses. The extent to which this occurs is an indication of fear memory formation: the stronger the response during learning, the stronger the fear response will be in the long term.

These findings may lead to greater insights into the formation of emotional memory. As a result, it is possible to conduct experimental research into the mechanisms that strengthen, weaken or even erase fear memory in a more direct fashion, without having to wait until the fear memory is expressed.

Researchers Identify Possible Treatment Window for Memory Problems

Researchers have identified a possible treatment window for plaques in the brain that are thought to cause memory loss in diseases such as Alzheimer’s, according to a new study published in the February 27, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Our study suggests that plaques in the brain that are linked to a decline in memory and thinking abilities, called beta amyloid, take about 15 years to build up and then plateau,” said Clifford R. Jack, Jr., MD, with the Mayo Clinic in Rochester, Minn.

For the study, 260 people between the ages of 70 and 92 underwent two or more brain scans over an average of 1.3 years that measured plaque buildup in the brain. Of the participants, 78 percent did not have impaired thinking abilities or memory at the start of the study.

The study found that the rate of buildup accelerates initially, then slows down before plateauing at high levels. For example, lower rates of plaque buildup were found in both people who had low and high levels of the plaques at the start of the study while the rate of plaque accumulation was highest in participants with mid-range levels at the start of the study.

The study also found that the rate of buildup of plaques was more closely tied to the total amount of amyloid plaques in the brain than other risk factors, such as the level of cognitive impairment, age and the presence of the APOE gene, a gene linked to Alzheimer’s disease.

“Our results suggest that there is a long treatment window where medications may be able to help slow buildup of the amyloid plaques that are linked to cognitive decline,” said Jack. “On the other hand, trying to treat the plaque buildup after the amyloid plaque load has plateaued may not do much good.”

Infant brains imply adult ills: Researchers study traits in babies as young as two weeks

Brain images from newborns are giving scientists a glimpse of the future - not just into the lives of their tiny subjects but also paths to treatment for adult patients with schizophrenia and Alzheimer’s disease.

Researchers from the University of North Carolina-Chapel Hill found degeneration in the brains of 2-week-old infants, a result considered a “game changer” for the field of brain research, said Jay Giedd, a brain imaging specialist for the National Institute of Mental Health.

"Our original model was that the brain was fine until someone got the illness," Giedd said. "This work shows that these changes are there probably from conception. It also suggests that while these traits don’t cause brain damage, they set up the brain to be slightly different."

The researchers examined scans of 272 newborns. About 15 percent were found to have smaller medial temporal lobe sections. “The medial temporal lobe plays an important role in memory,” said Rebecca Knickmeyer, a UNC assistant professor of psychiatry and co-author of the research, published last month in Cerebral Cortex, an online journal.

"The idea is that this is an anatomical vulnerability. If you start out with less, you might hit active symptoms earlier in life."

The researchers also found specific gene traits associated with Alzheimer’s in babies with the smaller media temporal lobes.

"We were interested because it was generally known that people’s genes contribute to psychiatric conditions later in life, but pretty much all the existing studies were in adults," Knickmeyer said. "Our question was ‘When were these genes exerting their effect?’ Now we know it’s much earlier than previously thought, perhaps before birth."

Research such as this would benefit from the Brain Activity Map under development through the National Institutes of Health. The project’s 10-year goal is to create a map of the brain’s nearly 30,000 genes as well as the circuitry system that transmits information via brain waves.

President Obama mentioned the project in his State of the Union address and is expected to include funding for the project in the upcoming federal budget. Foundations and some private companies have also expressed interest in assisting in the project, which is expected to push brain research to a higher level.

"As brain scientists, we were giddy to hear this," Giedd said. "Motivation is sky high. If they fund this, we believe our work will really take off." Giedd, who is familiar with but did not participate in the infant brain study, said the search for treatments or cures for diseases such as Alzheimer’s, autism, schizophrenia and Parkinson’s disease have been stymied by the many mysteries that remain regarding how the brain functions.

"If we understood more about the mechanisms that cause these diseases, we could step in and do something about it," Giedd said. "The brain is so complicated. Most diseases don’t just involve one or two or even three genes. It might be 60 or 100 genes, along with upbringing, diet and environment. There are so many parameters to the equation."

Knickmeyer said her research team plans to follow up with the newborns as they grow into adulthood to see whether the traits displayed by infants change over time or remain stable throughout their lives.

Daniel Kaufer, cognitive neurology and memory disorders chief for UNC’s Department of Neurology, said he thinks the time is right for great advances in brain research.

"We are at the crossroads of two important events: the realization that brain disorders may occur long before symptoms begin, and the development of brain imaging technology to record brain processes," Kaufer said.

Learning more about the brain’s functions through gene mapping may be the third piece of the puzzle. “Right now, there is no map of the human brain,” said Murali Doraiswamy, professor of psychiatry and behavioral sciences at Duke University School of Medicine.

Doraiswamy said the brain carries thousands of genes that influence thought, perception, emotion, memory and other mental activities. “We want to find out how much is nature and how much is nurture,” he added. “I think we are at the forefront of something very insightful, but also a little frightening.”

MAPPING A NEW WORLD

The Brain Activity Map is being planned as a decade-long research effort to create a comprehensive outline of the structure of the human brain and its neurons.

Funding is expected to come from a variety of sources, including the federal government, private industry and research foundations.

Details of the project have not yet been made public. But it is being compared to the DNA sequencing effort known as the Human Genome Project, which ran from 1990 to 2003 and cost $3.8 billion.

Discovery on animal memory opens doors to research on memory impairment diseases

If you ask a rat whether it knows how it came to acquire a certain coveted piece of chocolate, Indiana University neuroscientists conclude, the answer is a resounding, “Yes.” A study newly published in the journal Current Biology offers the first evidence of source memory in a nonhuman animal.

The findings have “fascinating implications,” said principal investigator Jonathon Crystal, both in evolutionary terms and for future research into the biological underpinnings of memory, as well as the treatment of diseases marked by memory failure such as Alzheimer’s, Parkinson’s and Huntington’s, or disorders such as schizophrenia, PTSD and depression.

The study further opens up the possibility of creating animal models of memory disorders.

"Researchers can now study in animals what was once thought an exclusively human domain," said Crystal, professor in the Department of Psychological and Brain Sciences in the College of Arts and Sciences. "If you can export types of behaviors such as source memory failures to transgenic animal models, you have the ability to produce preclinical models for the treatment of diseases such as Alzheimer’s."

Of the various forms of memory identified by scientists, some have long been considered distinctively human. Among these is source memory. When someone retells a joke to the person who told it to him, it is an everyday example of source memory failure. The person telling the joke forgot the source of the information — how he acquired it — though not the information he was told. People combine source information to construct memories of discrete events and to distinguish one event or episode from another.

Nonhuman animals, by contrast, have been thought to have limited forms of memory, acquired through conditioning and repetition, habits rather than conscious memories. The kind of memory failures most devastating to those directly affected by Alzheimer’s have typically been considered beyond the scope of nonhuman minds.

The study owes much to another quality these rodents share with humans: They love chocolate. “There’s no amount of chocolate you can give to a rat which will stop it from eating more chocolate,” Crystal said.

Linking insulin to learning: Important insights in research with worms

Recent work by Harvard researchers demonstrates how the signaling pathway of insulin and insulinlike peptides plays a critical role in helping to regulate learning and memory.

The research, led by Yun Zhang, associate professor of organismic and evolutionary biology, is described in a Feb. 6 paper in Neuron.

“People think of insulin and diabetes, but many metabolic syndromes are associated with some types of cognitive defects and behavioral disorders, like depression or dementia,” Zhang said. “That suggests that insulin and insulinlike peptides may play an important role in neural function, but it’s been very difficult to nail down the underlying mechanism, because these peptides do not have to function through synapses that connect different neurons in the brain.”

To get at that mechanism, Zhang and colleagues turned to an organism whose genome and nervous system are well described and highly accessible by genetics: C. elegans.

Using genetic tools, researchers altered the transparent worms by removing their ability to create individual insulinlike compounds. These new “mutant” worms were then tested to see whether they would learn to avoid eating a particular type of bacteria that is known to infect the worms. Tests showed that although some worms did learn to steer clear of the bacteria, others didn’t — suggesting that removing a specific insulinlike compound halted the worms’ ability to learn.

Researchers were surprised to find, however, that it wasn’t just removing the molecules that could make the animals lose the ability to learn — some peptides were found to inhibit learning.

“We hadn’t predicted that we would find both positive and negative regulators from these peptides,” Zhang said. “Why does the animal need this bidirectional regulation of learning? One possibility is that learning depends on context. There are certain things you want to learn — for example, the worms in these experiments wanted to learn that they shouldn’t eat this type of infectious bacteria. That’s a positive regulation of the learning. But if they needed to eat, even if it is a bad food, to survive, they would need a way to suppress this type of learning.”

Even more surprising for Zhang and her colleagues was evidence that the various insulinlike molecules could regulate each other.

“Many animals, including humans, have multiple insulinlike molecules, and it appears that these molecules can act like a network,” she said. “Each of them may play a slightly different role in the nervous system, and they function together to coordinate the signaling related to learning and memory. By changing the way the molecules interact, the brain can fine-tune learning in a host of different ways.”