Scientists identify molecular system that could help develop potential treatments for conditions such as Alzheimer’s disease

Scientists from the University of Southampton have identified the molecular system that contributes to the harmful inflammatory reaction in the brain during neurodegenerative diseases.

An important aspect of chronic neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s or prion disease, is the generation of an innate inflammatory reaction within the brain.

Results from the study open new avenues for the regulation of the inflammatory reaction and provide new insights into the understanding of the biology of microglial cells, which play a leading role in the development and maintenance of this reaction.

Dr Diego Gomez-Nicola, from the CNS Inflammation group at the University of Southampton and lead author of the paper, says: “The understanding of microglial biology during neurodegenerative diseases is crucial for the development of potential therapeutic approaches to control the harmful inflammatory reaction. These potential interventions could modify or arrest neurodegenerative diseases like Alzheimer disease.

“The future potential outcomes of this line of research would be rapidly translated into the clinics of neuropathology, and would improve the quality of life of patients with these diseases.”

Microglial cells multiply during different neurodegenerative conditions, although little is known about to what extent this accounts for the expansion of the microglial population during the development of the disease or how it is regulated.

Writing in The Journal of Neuroscience, scientists from the University of Southampton describe how they used a laboratory model of neurodegeneration (murine prion disease), to understand the brain’s response to microglial proliferation and dissected the molecules regulating this process. They found that signalling through a receptor called CSF1R is a key for the expansion of the microglial population and therefore drugs could target this.

Dr Diego Gomez-Nicola adds: “We have been able to identify that this molecular system is active in human Alzheimer’s disease and variant Creutzfeldt–Jakob disease, pointing to this mechanism being universal for controlling microglial proliferation during neurodegeneration. By means of targeting CSF1R with selective inhibitors we have been able to delay the clinical symptoms of experimental prion disease, also preventing the loss of neurons.”

Circadian clock linked to obesity, diabetes and heart attacks

Disruption in the body’s circadian rhythm can lead not only to obesity, but can also increase the risk of diabetes and heart disease.

That is the conclusion of the first study to show definitively that insulin activity is controlled by the body’s circadian biological clock. The study, which was published on Feb. 21 in the journal Current Biology, helps explain why not only what you eat, but when you eat, matters.

The research was conducted by a team of Vanderbilt scientists directed by Professor of Biological Sciences Carl Johnson and Professors of Molecular Physiology and Biophysics Owen McGuinness and David Wasserman.

“Our study confirms that it is not only what you eat and how much you eat that is important for a healthy lifestyle, but when you eat is also very important,” said postdoctoral fellow Shu-qun Shi, who performed the experiment with research assistant Tasneem Ansari in the Vanderbilt University Medical Center’s Mouse Metabolic Phenotyping Center.

In recent years, a number of studies in both mice and men have found a variety of links between the operation of the body’s biological clock and various aspects of its metabolism, the physical and chemical processes that provide energy and produce, maintain and destroy tissue. It was generally assumed that these variations were caused in response to insulin, which is one of the most potent metabolic hormones. However, no one had actually determined that insulin action follows a 24-hour cycle or what happens when the body’s circadian clock is disrupted.

Because they are nocturnal, mice have a circadian rhythm that is the mirror image of that of humans: They are active during the night and sleep during the day. Otherwise, scientists have found that the internal timekeeping system of the two species operate in nearly the same way at the molecular level. Most types of cells contain their own molecular clocks, all of which are controlled by a master circadian clock in the suprachiasmatic nucleus in the brain.

“People have suspected that our cells’ response to insulin had a circadian cycle, but we are the first to have actually measured it,” said McGuinness. “The master clock in the central nervous system drives the cycle and insulin response follows.”

Cooling may prevent trauma-induced epilepsy

In the weeks, months and years after a severe head injury, patients often experience epileptic seizures that are difficult to control. A new study in rats suggests that gently cooling the brain after injury may prevent these seizures.

“Traumatic head injury is the leading cause of acquired epilepsy in young adults, and in many cases the seizures can’t be controlled with medication,” says senior author Matthew Smyth, MD, associate professor of neurological surgery and of pediatrics at Washington University School of Medicine in St. Louis. “If we can confirm cooling’s effectiveness in human trials, this approach may give us a safe and relatively simple way to prevent epilepsy in these patients.”

The researchers reported their findings in Annals of Neurology.

Cooling the brain to protect it from injury is not a new concept. Cooling slows down the metabolic activity of nerve cells, and scientists think this may make it easier for brain cells to survive the stresses of an injury. 

Doctors currently cool infants whose brains may have had inadequate access to blood or oxygen during birth. They also cool some heart attack patients to reduce peripheral brain damage when the heart stops beating.

Smyth has been exploring the possibility of using cooling to prevent seizures or reduce their severity.

“Warmer brain cells seem to be more electrically active, and that may increase the likelihood of abnormal electrical discharges that can coalesce to form a seizure,” Smyth says. “Cooling should have the opposite effect.”

Smyth and colleagues at the University of Washington and the University of Minnesota test potential therapies in a rat model of brain injury. These rats develop chronic seizures weeks after the injury.

Researchers devised a headset that cools the rat brain. They were originally testing its ability to stop seizures when they noticed that cooling seemed to be not only stopping but also preventing seizures.

Scientists redesigned the study to focus on prevention. Under the new protocols, they put headsets on some of the rats that cooled their brains by less than 4 degrees Fahrenheit. Another group of rats wore headsets that did nothing. Scientists who were unaware of which rats they were observing monitored them for seizures during treatment and after the headsets were removed.

Rats that wore the inactive headset had progressively longer and more severe seizures weeks after the injury, but rats whose brains had been cooled only experienced a few very brief seizures as long as four months after injury.

Brain injury also tends to reduce cell activity at the site of the trauma, but the cooling headsets restored the normal activity levels of these cells.

The study is the first to reduce injury-related seizures without drugs, according to Smyth, who is director of the Pediatric Epilepsy Surgery program at St. Louis Children’s Hospital.

“Our results show that the brain changes that cause this type of epilepsy happen in the days and weeks after injury, not at the moment of injury or when the symptoms of epilepsy begin,” says Smyth. “If clinical trials confirm that cooling has similar effects in humans, it could change the way we treat patients with head injuries, and for the first time reduce the chance of developing epilepsy after brain injury.”

Smyth and his colleagues have been testing cooling devices in humans in the operating room, and are planning a multi-institutional trial of an implanted focal brain cooling device to evaluate the efficacy of cooling on established seizures.

Where does our head come from?

A research group at the Sars Centre in Bergen has shed new light on the evolutionary origin of the head. In a study published in the journal PLoS Biology they show that in a simple, brainless sea anemone, the same genes that control head development in higher animals regulate the development of the front end of the swimming larvae.

In many animals, the brain is located in a specific structure, the head, together with sensory organs and often together with the mouth. However, there are even more distantly related animals, which have a nervous system, but no brain, like sea anemones and corals.
In this study a research group led by Fabian Rentzsch used the sea anemone Nematostella vectensis to find out if one of the ends of the sea anemone corresponds to the head of higher animals. To do this they studied the function of genes that control head development in higher animals during the embryonic development of the starlet sea anemone.

“Despite looking completely different, it has become clear over the last decade, that all animals have a similar repertoire of genes, including those that are required to make the head of higher animals”, says first author and PhD-student Chiara Sinigaglia.

Stands on its head
When the sea anemone is in the larval stage it swims. As adults, the sea anemone stands with one end on the sea floor and uses long tentacles on its upper end to catch small animals which they stuff into the only body opening in the middle of the ring of tentacles.

“Based on the appearance of the adult animals, the lower end of these animals has traditionally been called the foot and the upper end the head”, explains Rentzsch.
What the research group found out was that in the sea anemone the “head gene” function is located at the end that corresponds to the “foot” of the adult animals. The key was to study the larvae of the sea anemones when theystill move around.

“The larvae swims with the “foot” end forward and this end carries their main sense organ, so at this stage it looks more like this might be their head”, says Rentzsch. And indeed, the “head genes” function on this side of the animals.
Sea anemones and all higher animals, including humans, share a common brainless ancestor which lived between 600 and 700 million years ago.

“By revealing the function of “head genes” in Nematostella, we now understand better how and from where the head and brain of higher animals evolved”, Sinigaglia and Rentzsch explain.

Clues to Fetal Alcohol Risk: Molecular switch promises new targets for diagnosis and therapy

Fetal alcohol syndrome is the leading preventable cause of developmental disorders in developed countries. And fetal alcohol spectrum disorder (FASD), a range of alcohol-related birth defects that includes fetal alcohol syndrome, is thought to affect as many as 1 in 100 children born in the United States.

Any amount of alcohol consumed by the mother during pregnancy poses a risk of FASD, a condition that can include the distinct pattern of facial features and growth retardation associated with fetal alcohol syndrome as well as intellectual disabilities, speech and language delays, and poor social skills. But drinking can have radically different outcomes for different women and their babies. While twin studies have suggested a genetic component to susceptibility to FASD, researchers have had little success identifying who is at greatest risk or what genes are at play.

Research from Harvard Medical School and Veterans Affairs Boston Healthcare System sheds new light on this question, identifying for the first time a signaling pathway that might determine genetic susceptibility for the development of FASD. The study was published online Feb. 19 in the journal Proceedings of the National Academy of Sciences.

“Our work points to candidate genes for FASD susceptibility and identifies a path for the rational development of drugs that prevent ethanol neurotoxicity,” said Michael Charness, chief of staff at VA Boston Healthcare System and HMS professor of neurology. “And importantly, identifying those mothers whose fetuses are most at risk could help providers better target intensive efforts at reducing drinking during pregnancy.”

The discovery also solves a riddle that had intrigued Charness and other researchers for nearly two decades. In 1996, Charness and colleagues discovered that alcohol disrupted the work of a human protein critical to fetal neural development—a major clue to the biological processes of FASD. The protein, L1, projects through the surface of a cell to help it adhere to its neighbors. When Charness and his team introduced the protein to a culture of mouse fibroblasts cells, L1 increased cell adhesion. Tellingly, the effect was erased in the presence of ethanol (beverage alcohol).

Charness and his team went on to develop multiple cell lines from that first culture, and that’s where they encountered the riddle: In some of those lines, alcohol disrupted L1’s adhesive effect, while in others it did not.

“How could it be possible that a cell that expresses L1 is completely sensitive to alcohol, and others that express it are completely insensitive?” asked Charness, who is also faculty associate dean for veterans hospital programs at HMS and assistant dean at Boston University School of Medicine.

Clearly, something else was affecting the protein’s sensitivity to alcohol — but what? Studies of twins provided one clue: Identical twins are more likely than fraternal twins to have the same diagnosis, positive or negative, for FASD. “That concordance suggests that there are modifying genes, susceptibility genes, that predispose to this condition,” Charness said.

Bilingual children have a better “working memory” than monolingual children

A study conducted at the University of Granada and the University of York in Toronto, Canada, has revealed that bilingual children develop a better working memory –which holds, processes and updates information over short periods of time– than monolingual children. The working memory plays a major role in the execution of a wide range of activities, such as mental calculation (since we have to remember numbers and operate with them) or reading comprehension (given that it requires associating the successive concepts in a text).

The objective of this study –which was published in the last issue of the Journal of Experimental Child Psychology– was examining how multilingualism influences the development of the “working memory” and investigating the association between the working memory and the cognitive superiority of bilingual people found in previous studies.

Executive Functions

The working memory includes the structures and processes associated with the storage and processing of information over short periods of time. It is one of the components of the so-called “executive functions”: a set of mechanisms involved in the planning and self-regulation of human behavior. Although the working memory is developed in the first years of life, it can be trained and improved with experience.

According to the principal investigator of this study, Julia Morales Castillo, of the Department of Experimental Psychology of the University of Granada, this study contributes to better understand cognitive development in bilingual and monolingual children. “Other studies have demonstrated that bilingual children are better at planning and cognitive control (i.e. tasks involving ignoring irrelevant information or requiring a dominant response). But, to date, there was no evidence on the influence of bilingualism on the working memory.

The study sample included bilingual children between 5 and 7 years of age (a critical period in the development of the working memory). The researchers found that bilingual children performed better than monolingual children in working memory tasks. Indeed, the more complex the tasks the better their performance. “The results of this study suggest that bilingualism does not only improve the working memory in an isolated way, but they affect the global development of executive functions, especially when they have to interact with each other”, Morales Castillo states.

Music Education

According to the researcher, the results of this study “contribute to the growing number of studies on the role of experience in cognitive development”. Other studies have demonstrated that children performing activities such as music education have better cognitive capacities. “However, we cannot determine to what extent children perform these activities due to other factors such as talent or personal interest”.

“However, the children in our study were bilingual because of family reasons rather than because of an interest in languages.

Children With Brain Lesions Able To Use Gestures Important To Language Learning

Children with brain lesions suffered before or around the time of birth are able to use gestures – an important aspect of the language learning process– to convey simple sentences, a Georgia State University researcher has found.

Şeyda Özçalışkan, assistant professor of psychology, and fellow researchers at the University of Chicago, looked at children who suffered lesions to one side of the brain to see whether they used gestures similar to typically developing children. She examined gestures such as pointing to a cookie while saying “eat” to convey the meaning “eat cookie,” several months before expressing such sentences exclusively in speech.

“We do know that children with brain injuries show an amazing amount of plasticity (the ability to change) for language learning if they acquire lesions early in life,” Özçalışkan said. “However, we did not know whether this plasticity was characterized by the same developmental trajectory shown for typically developing children, with gesture leading the way into speech.  We looked at the onset of different sentence constructions in children with early brain injuries, and wanted to find out if we could see precursors of different sentence types in gesture.

“For children with brain injuries, we found that this pattern holds, similar to typically developing children,” she said. “Children with unilateral brain injuries produce different kinds of simple sentences several months later than typically developing children. More important, the delays we observe in producing different sentences in speech are preceded by a similar delay in producing the same sentences in gesture-speech combinations.”

Children with brain injuries also had a more difficult time in producing complex sentences across gesture and speech, such as conveying relationships between actions, for example saying “help me do it” while making a painting gesture.

“This in turn was later reflected in a much narrower range of complex sentence types expressed in their speech,” Özçalışkan said. “This suggested to us, in general, that producing sentences across gesture and speech may serve as an embodied sensorimotor experience, that might help children take the next developmental step in producing these sentences in speech.

“And if you bypass the gesture-speech combination stage, that might negatively affect developing a broader representation of complex sentence types in speech.”

The researchers also compared children with smaller brain lesions against children with large lesions, and found more of a delay in producing sentences, both in speech and in gesture-speech combinations, in children with large lesions.

The research has implications for developing interventions to help children with the language learning process, “as it shows that gestures are integral to the process of language learning even when that learning is taking place in an injured brain,” Özçalışkan said.

“When children do different kinds of sentence combinations across gesture and speech, that’s like a signal to the caregiver that ‘I’m ready for this,’” she said. “The caregiver can then provide relevant input to the child, and that could in turn help the child take the next developmental step in producing that sentence entirely in speech.”

Genome-wide imaging study identifies new gene associated with Alzheimer’s plaques

A study combining genetic data with brain imaging, designed to identify genes associated with the amyloid plaque deposits found in Alzheimer’s disease patients, has not only identified the APOE gene — long associated with development of Alzheimer’s — but has uncovered an association with a second gene, called BCHE.

A national research team, led by scientists at the Indiana University School of Medicine, reported the results of the study in an article in Molecular Psychiatry posted online Tuesday. The study is believed to be the first genome-wide association study of plaque deposits using a specialized PET scan tracer that binds to amyloid.

The research also is believed to be the first to implicate variations in the BCHE gene in plaque deposits visualized in living individuals who have been diagnosed with Alzheimer’s disease or are at-risk for developing the disease. The enzyme coded by the BCHE gene has previously been studied in post-mortem brain tissue and is known to be found in plaques.

“The findings could recharge research efforts studying the molecular pathways contributing to amyloid deposits in the brain as Alzheimer’s disease develops and affects learning and memory,” said Vijay K. Ramanan, the paper’s first author and an M.D./Ph.D. student at the IU School of Medicine.

The BCHE gene finding “brings together two of the major hypotheses about the development of Alzheimer’s disease,” said Andrew J. Saykin, Psy.D., Raymond C. Beeler Professor of Radiology and Imaging Sciences at IU and principal investigator for the genetics core of the Alzheimer’s Disease Neuroimaging Initiative.

Scientists have long pointed to the loss of an important brain neurotransmitter, acetylcholine, which is depleted early in the development of the disease, as a key aspect of the loss of memory related neurons. The BCHE gene is responsible for an enzyme that breaks down acetylcholine in the brain. The other major Alzheimer’s hypothesis holds that the development of the amyloid plaques is the primary cause of the disease’s debilitating symptoms. As it turns out, the enzyme for which the BCHE gene codes is also found in significant quantities in those plaques.

“This study is connecting two of the biggest Alzheimer’s dots,” said Dr. Saykin, director of the Indiana Alzheimer Disease Center and the IU Center for Neuroimaging at the IU Health Neuroscience Center.

“The finding that BCHE gene variant predicts the extent of plaque deposit in PET scans among people at risk for Alzheimer’s disease is likely to reinvigorate research into drugs that could modify the disease by affecting the BCHE enzyme or its metabolic pathway,” he said. Some existing drugs inhibit this enzyme, but it is unclear whether this influences plaque deposits.

Overall, the results appear to offer scientists new potential targets for drugs to slow, reverse or even prevent the disease. Alzheimer’s disease affects an estimated 5.4 million Americans and has proven resistant to treatments that do more than temporarily slow the worsening of symptoms.

Amyloid plaque deposits build up abnormally in the brains of Alzheimer’s patients and are believed to play an important role in the memory loss and other problems that plague patients.

The study makes use of an imaging agent, florbetapir, now approved for use by the U.S. Food and Drug Administration, that allows physicians to see the level of plaque buildup in a patient’s brain, something that previously could be determined only with an autopsy.

In a genome-wide association study, researchers evaluate alternate versions of many genes to determine whether particular genetic variants are associated with a particular trait — in this case, the amounts of amyloid plaque deposits that the PET scans revealed in the brains of study participants.

Using the imaging agent that enables detection of the plaques in the brain, the researchers conducted PET scans of 555 participants in the Alzheimer’s Disease Neuroimaging Initiative, a long-term public-private research project that includes people at risk for Alzheimer’s disease and patients who have been diagnosed with the disease as well as participants with no symptoms.

With sophisticated statistical analyses, the imaging data was combined with analyses of DNA collected from the 555 participants to determine whether particular gene variants were found more often among patients with higher levels of plaque deposits.

The analysis found that a variant in BCHE was significantly associated with the levels of plaque deposits. As would be expected, the analysis also found a strong association with variants of another gene, APOE, that has long been known to be associated with the development of Alzheimer’s. The effect of BCHE was independent of APOE, however. Moreover, the effects of the two genes were additive — that is, people with the suspect variants of both genes had more plaque deposits than people who had only one of the variants associated with plaque development.

Omega-3 Lipid Emulsions Markedly Protect Brain After Stroke in Mouse Study

Triglyceride lipid emulsions rich in an omega-3 fatty acid injected within a few hours of an ischemic stroke can decrease the amount of damaged brain tissue by 50 percent or more in mice, reports a new study by researchers at Columbia University Medical Center.

The results suggest that the emulsions may be able to reduce some of the long-term neurological and behavioral problems seen in human survivors of neonatal stroke and possibly of adult stroke, as well. The findings were published today in the journal PLoS One.

Currently, clot-busting tPA (recombinant tissue-type plasminogen activator) is the only treatment shown to improve recovery from ischemic stroke. If administered soon after stroke onset, the drug can restore blood flow to the brain but may not prevent injured, but potentially salvageable, neurons from dying.

Drugs with neuroprotective qualities that can prevent the death of brain cells damaged by stroke are needed, but even after 30 years of research and more than 1000 agents tested in animals, no neuroprotectant has been found effective in people.

Omega-3 fatty acids may have more potential as neuroprotectants because they affect multiple biochemical processes in the brain that are disturbed by stroke, said the study’s senior author, Richard Deckelbaum, MD, director of the Institute of Human Nutrition at Columbia’s College of Physicians & Surgeons. “The findings also may be applicable to other causes of ischemic brain injury in newborns and adults,” added co-investigator Vadim S. Ten, MD, PhD, an associate professor of pediatrics from the Department of Pediatrics at Columbia.

The effects of the omega-3 fatty acids include increasing the production of natural neuroprotectants in the brain, reducing inflammation and cell death, and activating genes that may protect brain cells. Omega-3 fatty acids also markedly reduce the release of harmful oxidants into the brain after stroke. “In most clinical trials in the past, the compounds tested affected only one pathway. Omega-3 fatty acids, in contrast, are very bioactive molecules that target multiple mechanisms involved in brain death after stroke,” Dr. Deckelbaum said.

The study revealed that an emulsion containing only DHA (docosahexaenoic acid), but not EPA (eicosapentaenoic acid), in a triglyceride molecule reduced the area of dead brain tissue by about 50 percent or more even when administered up to two hours after the stroke. Dr. Deckelbaum noted, “Since mice have a much faster metabolism than humans, longer windows of time for therapeutic effect after stroke are likely in humans.” Eight weeks after the stroke, much of the “saved” mouse brain tissue was still healthy, and no toxic effects were detected.

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