Potential New Autism Drug Shows Promise in Mice

Scientists have performed a successful test of a possible new drug in a mouse model of an autism disorder. The candidate drug, called NitroSynapsin, largely corrected electrical, behavioral and brain abnormalities in the mice.

NitroSynapsin is intended to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).

“This drug candidate is poised to go into clinical trials, and we think it might be effective against multiple forms of autism,” said senior investigator Stuart Lipton, M.D., Ph.D., Professor and Hannah and Eugene Step Chair at The Scripps Research Institute (TSRI), who is also a clinical neurologist caring for patients.

The research, published on today in the journal Nature Communications, was a collaboration involving scientists at the Scintillon Institute; the University of California, San Diego School of Medicine; Sanford Burnham Prebys Medical Discovery Institute and other institutions. Lipton’s fellow senior investigators on the project were Drs. Nobuki Nakanishi and Shichun Tu of the Scintillon Institute in San Diego.

ASD is brain development disorder that affects 1 in 68 children in the United States alone. Because ASD has been diagnosed more often in recent years, most Americans now living with autism diagnoses are children—roughly 2.4 percent of boys and 0.5 percent of girls.

Genetic Analysis Leads to Potential Treatment

The new study stemmed from a 1993 study in which Lipton and his laboratory, then at Harvard Medical School, identified a gene called MEF2C as a potentially important factor in brain development.

This breakthrough led Lipton and colleagues to the discovery that disrupting the mouse version of MEF2C in the brain, early in fetal development, causes mice to be born with severe, autism-like abnormalities. Since that discovery in mice in 2008, other researchers have reported many cases of children who have a very similar disorder, resulting from a mutation to one copy of MEF2C (human DNA normally contains two copies of every gene, one copy inherited from the father and one from the mother). The condition is now called MEF2C Haploinsufficiency Syndrome (MHS).

“This syndrome was discovered in people only because it was first discovered in mice—it’s a good example of why basic science is so important,” Lipton said.

MEF2C encodes a protein that works as a transcription factor, like a switch that turns on the expression of many genes. Although MHS accounts for only a small proportion of autism disorder cases, large-scale genomic studies in recent years have found that mutations underlying various autism disorders frequently involve genes whose activity is switched on by MEF2C.

“Because MEF2C is important in driving so many autism-linked genes, we’re hopeful that a treatment that works for this MEF2C-haploinsufficiency syndrome will also be effective against other forms of autism,” Lipton said, “and in fact we already have preliminary evidence for this.”

For the study, the researchers created a laboratory model of MHS by engineering mice to have—like human children with MHS—just one functioning copy of the mouse version of MEF2C, rather than the usual two copies. The mice showed impairments in spatial memory, abnormal anxiety and abnormal repetitive movements, plus other signs consistent with human MHS. Analyses of mouse brains revealed a host of problems, including an excess in key brain regions of excitatory signaling (which causes neurons to fire) over inhibitory signaling (which suppresses neuronal activity).

In short, these two important kinds of brain signals were out of balance. A similar excitatory/inhibitory (E/I) imbalance is seen in most forms of ASD and is thought to explain many of the core features of these disorders, including cognitive and behavioral problems and an increased chance of epileptic seizures.

The researchers treated the MHS-mice for three months with NitroSynapsin, an aminoadamantane nitrate compound related to the Alzheimer’s FDA-approved drug memantine, which was previously developed by Lipton’s group. NitroSynapsin is known to help reduce excess excitatory signaling in the brain, and the team found that the compound did reduce the E/I imbalance and also reduced abnormal behaviors in the mice and boosted their performance on cognitive/behavioral tests—in some cases restoring performance essentially to normal.

Lipton and colleagues are currently testing the drug in mouse models of other autism disorders, and they hope to move NitroSynapsin into clinical trials with a biotechnology partner.

The work also has support from parents of children with MHS. “We are all hanging on to the hope that one day our children will be able to speak, to understand and to live more independent lives,” said Michelle Dunlavy, who has a son with MHS.

In fact, Lipton’s group is also now using stem cell technology to create cell-based models of MHS with skin cells from children who have the syndrome—and NitroSynapsin appears to work in this ‘human context’ as well. Dunlavy and other parents of children with MHS recently organized an international, Facebook-based support group, which is coordinating to assist in Lipton’s research going forward.

In an amazing twist, the scientific team also found in Alzheimer’s disease models that the new NitroSynapsin compound improves synapse function, the specialized areas for communication between nerve cells. Thus, the ability of the drug to improve ‘network’ communication in the brain may eventually lead to its use in several neurological diseases.

New Player in Alzheimer’s Disease Pathogenesis Identified

Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have shown that a protein called membralin is critical for keeping Alzheimer’s disease pathology in check. The study, published in Nature Communications, shows that membralin regulates the cell’s machinery for producing beta-amyloid (or amyloid beta, Aβ), the protein that causes neurons to die in Alzheimer’s disease.

“Our results suggest a new path toward future treatments for Alzheimer’s disease,” says Huaxi Xu, Ph.D., the Jeanne and Gary Herberger Leadership Chair of SBP’s Neuroscience and Aging Research Center. “If we can find molecules that modulate membralin, or identify its role in the cellular protein disposal machinery known as the endoplasmic reticulum-associated degradation (ERAD) system, this may put the brakes on neurodegeneration.”

ERAD is the mechanism by which cells get rid of proteins that are folded incorrectly in the ER. It also controls the levels of certain mature, functional proteins. Xu’s team found that one of the fully formed, working proteins that ERAD regulates is a component of an enzyme called gamma secretase that generates Aβ.

This discovery helps fill in the picture of how Alzheimer’s disease, an incredibly complicated disorder influenced by many genetic and environmental factors. No therapies have yet been demonstrated to slow progression of the disease, which affects around 47 million people worldwide. Until such drugs are developed, patients face a steady, or sometimes rapid, decline in memory and reasoning.

Memory loss in Alzheimer’s results from the toxic effects of Aβ, which causes connections between neurons to break down. Aβ is created when gamma secretase cuts the amyloid precursor protein into smaller pieces. While Aβ is made in all human brains as they age, differences in the rate at which it is produced and eliminated from the brain and in how it affects neurons, means that not everyone develops dementia.

“We were interested in membralin because of its genetic association with Alzheimer’s, and in this study we established the connection between membralin and Alzheimer’s based on findings from the laboratory of a former colleague at SBP, Professor Dongxian Zhang,” Xu explains. “That investigation showed that eliminating the gene for membralin leads to rapid motor neuron degeneration, but its cellular function wasn’t clear.”

Using proteomics, microscopic analysis, and functional assays, the group provided definitive evidence that membralin functions as part of the ERAD system. Later, they found that membralin-dependent ERAD breaks down a protein that’s part of the gamma secretase enzyme complex, and that reducing the amount of membralin in a mouse model of Alzheimer’s exacerbates neurodegeneration and memory problems.

“Our findings explain why mutations that decrease membralin expression would increase the risk for Alzheimer’s,” Xu comments. “This would lead to an accumulation of gamma secretase because its degradation is disabled, and the gamma-secretase complex would then generate more Aβ. Those mutations are rare, but there may be other factors that cause neurons to make less membralin.”

Xu and colleagues also observed lower levels of membralin, on average, in the brains of patients with Alzheimer’s than in unaffected individuals, demonstrating the relevance of their findings to humans.

“Previous studies have suggested that ERAD contributes to many diseases where cells become overwhelmed by an irregular accumulation of proteins, including Alzheimer’s,” says Xu. “This study provides conclusive, mechanistic evidence that ERAD plays an important role in restraining Alzheimer’s disease pathology. We now plan to search for compounds that enhance production of membralin or the rate of ERAD to test whether they ameliorate pathology and cognitive decline in models of Alzheimer’s. That would further support the validity of this mechanism as a drug target.”

Predicting Autism: Researchers Find Autism Biomarkers in Infancy

By using magnetic resonance imaging (MRI) to study the brains of infants who have older siblings with autism, scientists were able to correctly identify 80 percent of the babies who would be subsequently diagnosed with autism at 2 years of age.

Researchers from the University of Washington were part of a North American effort led by the University of North Carolina to use MRI to measure the brains of “low-risk” infants, with no family history of autism, and “high-risk” infants who had at least one autistic older sibling. A computer algorithm was then used to predict autism before clinically diagnosable behaviors set in. The study was published Feb. 16 in the journal Nature.

This is the first study to show that it is possible to use brain biomarkers to identify which infants in a high-risk pool — that is, those having an older sibling with autism — will be diagnosed with autism spectrum disorder, or ASD, at 24 months of age.

“Typically, the earliest we can reliably diagnose autism in a child is age 2, when there are consistent behavioral symptoms, and due to health access disparities the average age of diagnosis in the U.S. is actually age 4,” said co-author and UW professor of speech and hearing sciences Annette Estes, who is also director of the UW Autism Center and a research affiliate at the UW Center on Human Development and Disability, or CHDD. “But in our study, brain imaging biomarkers at 6 and 12 months were able to identify babies who would be later diagnosed with ASD.”

The predictive power of the team’s findings may inform the development of a diagnostic tool for ASD that could be used in the first year of life, before behavioral symptoms have emerged.

“We don’t have such a tool yet,” said Estes. “But if we did, parents of high-risk infants wouldn’t need to wait for a diagnosis of ASD at 2, 3 or even 4 years and researchers could start developing interventions to prevent these children from falling behind in social and communication skills.”

People with ASD — which includes 3 million people in the United States — have characteristic social communication deficits and demonstrate a range of ritualistic, repetitive and stereotyped behaviors. In the United States, it is estimated that up to one out of 68 babies develops autism. But for infants with an autistic older sibling, the risk may be as high as one out of every five births.

This research project included hundreds of children from across the country and was led by researchers at four clinical sites across the United States: the University of North Carolina-Chapel Hill, UW, Washington University in St. Louis and The Children’s Hospital of Philadelphia. Other key collaborators are at the Montreal Neurological Institute, the University of Alberta and New York University.

“We have wonderful, dedicated families involved in this study,” said Stephen Dager, a UW professor of radiology and associate director of the CHDD, who led the study at the UW. “They have been willing to travel long distances to our research site and then stay up until late at night so we can collect brain imaging data on their sleeping children. The families also return for follow-up visits so we can measure how their child’s brain grows over time. We could not have made these discoveries without their wholehearted participation.”

Researchers obtained MRI scans of children while they were sleeping at 6, 12 and 24 months of age. The study also assessed behavior and intellectual ability at each visit, using criteria developed by Estes and her team. They found that the babies who developed autism experienced a hyper-expansion of brain surface area from 6 to 12 months, as compared to babies who had an older sibling with autism but did not themselves show evidence of autism at 24 months of age. Increased surface area growth rate in the first year of life was linked to increased growth rate of brain volume in the second year of life. Brain overgrowth was tied to the emergence of autistic social deficits in the second year.

The researchers input these data — MRI calculations of brain volume, surface area, and cortical thickness at 6 and 12 months of age, as well as sex of the infants — into a computer program, asking it to classify babies most likely to meet ASD criteria at 24 months of age. The program developed the best algorithm to accomplish this, and the researchers applied the algorithm to a separate set of study participants.

Researchers found that, among infants with an older ASD sibling, the brain differences at 6 and 12 months of age successfully identified 80 percent of those infants who would be clinically diagnosed with autism at 24 months of age.
If these findings could form the basis for a “pre-symptomatic” diagnosis of ASD, health care professionals could intervene even earlier.

“By the time ASD is diagnosed at 2 to 4 years, often children have already fallen behind their peers in terms of social skills, communication and language,” said Estes, who directs behavioral evaluations for the network. “Once you’ve missed those developmental milestones, catching up is a struggle for many and nearly impossible for some.”

Research could then begin to examine interventions on children during a period before the syndrome is present and when the brain is most malleable. Such interventions may have a greater chance of improving outcomes than treatments started after diagnosis.

“Our hope is that early intervention — before age 2 — can change the clinical course of those children whose brain development has gone awry and help them acquire skills that they would otherwise struggle to achieve,” said Dager.

The research team has gathered additional behavioral and brain imaging data on these infants and children — such as changes in blood flow in the brain and the movement of water along white matter networks — to understand how brain connectivity and neural activity may differ between high-risk children who do and don’t develop autism. In a separate study published Jan. 6 in Cerebral Cortex, the researchers identified specific brain regions that may be important for acquiring an early social behavior called joint attention, which is orienting attention toward an object after another person points to it.

“These longitudinal imaging studies, which follow the same infants as they grow older, are really starting to hone in on critical brain developmental processes that can distinguish children who go on to develop ASD and those who do not,” said Dager. “We hope these ongoing efforts will lead to additional biomarkers, which could provide the basis for early, pre-symptomatic diagnosis and serve also to guide individualized interventions to help these kids from falling behind their peers.”

Attractive Drug Candidate Identified to Target Glioma Brain Tumors

This rapidly fatal brain cancer has seen only two improvements in therapy in 30 years.

In a paper published today in Cancer Research, researchers: 1) identify a biomarker enzyme associated with aggressive glioma brain tumors, 2) reveal the regulatory mechanism for that enzyme, and 3) demonstrate potent efficacy, using a mouse model of glioma, for a small molecule inhibitor they have developed.

The inhibitor, GA11, retains a core structure that resembles natural inhibitors of the biomarker enzyme; but the inhibitor has been modified to help it pass through the blood-brain barrier.

“In principle, both these features make GA11 an attractive drug candidate to target glioma stem-like cells in glioblastoma multiforme tumors,” said Ichiro Nakano, M.D., Ph.D., and colleagues in the paper.

Nakano, a professor of neurosurgery and academic neurosurgeon at the University of Alabama at Birmingham, and Vito Coviello and Concettina La Motta, University of Pisa, Italy, are doing further preclinical evaluation of the GA11 and its analogs.

Glioblastoma multiforme, or GBM, is a formidable cancer foe. Only two therapeutic improvements have appeared in the past 30 years, increasing the average survival of patients from five months to 15 or 16 months, Nakano says.

A GBM tumor is a mix of different cells that respond differently to therapies. Small numbers of glioma stem-like cells, or GSCs, drive the tumorigenicity of GBM and thus are prime targets for possible treatments. One GSC subtype called the mesenchymal GSC is more malignant and the most therapy-resistant, so Nakano and fellow researchers reasoned that identifying the regulatory molecules active in mesenchymal GSCs might lead to novel and effective therapeutics.

Study details
Nakano and colleagues found that one form of the enzyme aldehyde dehydrogenase — ALDH1A3 — is a specific marker for mesenchymal GSCs, and his group is the first to show that, among the heterogeneous mix of cells in a GBM tumor, cells with high levels of ALDH1A3 expression were more tumorigenic in vivo than are cells that are low in ALDH1A3.

The researchers also found that the FOXD1 transcription factor regulates the production of ALDH1A3 in mesenchymal GSCs. In clinical samples of high-grade gliomas from patients, the expression levels of both FOXD1 and ALDH1A3 were inversely correlated with disease progression — gliomas with high levels were more rapidly fatal than were gliomas with low levels.

Astonishingly, the same mechanism that drives the mesenchymal GSC tumorigenicity in humans acts in an evolutionarily distant organism, the fruit fly. Knocking down the expression of either the fruit fly version of the FOXD1 gene or the fruit fly version of ALDH1A3 blocks the formation of brain tumors in a brain cancer model of the fruit fly species Drosophila melanogaster, the researchers found. Thus, this signaling has been highly conserved in evolution.

The FOXD1 transcription factor is normally active during development from a fertilized egg and embryo to a fetus, and it is silent after birth. The role of FOXD1 in GBM, Nakano and colleagues say, suggests that the mesenchymal GSCs have hijacked the molecular mechanism of normal embryonic development to promote tumor growth.

In preclinical testing, GA11 was validated several ways. The researchers showed that it inhibited ALDH in yeast, reduced ALDH1 activity in cell-culture spheres of mesenchymal GSCs, inhibited proliferation of glioma spheres in cell culture, and inhibited xenograft growth of GBM in mouse brains.

“In conclusion,” Nakano and fellow researchers wrote, “the FOXD1-ALDH1A3 axis is critical for tumor initiation in mesenchymal GSCs, therefore providing possible new molecular targets for the treatment of GBM and other ALDH1-activated cancers.”

Nakano says his study of the role of GSCs in GBM is just one approach to treat glioma tumors. Other labs are pursuing immunotherapy, the use of check-point inhibitors, vaccination and efforts to increase sensitivity to radiotherapy.

It will take combined therapies to treat glioblastoma, Nakano says. “We don’t believe that one therapy will be effective.”

Nakano expects to launch a new clinical trial for glioblastoma in 2017, in conjunction with Burt Nabors, M.D., professor of neurology at UAB. Nakano says UAB will be the only site in the Deep South for this unique trial aimed at a molecular target in glioma stem cells, a target that is different from the ones described in the Cancer Research paper. The referral contact to Nakano’s service will be Lydia P. Harrell.

The Nakano lab is also working on brain metastases, tumors that spread into the brain from other parts of the body. Similar to high-grade gliomas, which originate in the brain, these metastatic brain tumors are lethal, and there are very few therapeutic options. Nakano believes the core stem cell genes and signaling pathways are shared between gliomas and brain metastases.

“If so,” he said, “the molecular targets identified for gliomas are most likely essential in brain metastases. Studies are underway, and similar to the glioma therapy development, I am working to develop clinical trials for brain metastasis, together with medical oncologists Mansoor Saleh, M.D., Andres Forero, M.D., and others at UAB.”

Restoring The Sense Of Touch In Amputees Using Natural Signals Of The Nervous System

Scientists at the University of Chicago and Case Western Reserve University have found a way to produce realistic sensations of touch in two human amputees by directly stimulating the nervous system.

The study, published Oct. 26 in Science Translational Medicine (STM), confirms earlier research on how the nervous system encodes the intensity, or magnitude, of sensations. It is the second of two groundbreaking publications this month by University of Chicago neuroscientist Sliman Bensmaia, PhD, using neuroprosthetic devices to recreate the sense of touch for amputee or quadriplegic patients with a “biomimetic” approach that approximates the natural, intact nervous system.

On Oct. 13, in a separate publication from STM, Bensmaia and a team led by Robert Gaunt, PhD, from the University of Pittsburgh, announced that for the first time, a paralyzed human patient was able to experience the sense of touch through a robotic arm that he controls with his brain. In that study, researchers interfaced directly with the patient’s brain, through an electrode array implanted in the areas of the brain responsible for hand movements and for touch, which allowed the man to both move the robotic arm and feel objects through it.

The new study takes a similar approach in amputees, working with two male subjects who each lost an arm after traumatic injuries. In this case, both subjects were implanted with neural interfaces, devices embedded with electrodes that were attached to the median, ulnar and radial nerves of the arm. Those are the same nerves that would carry signals from the hand were it still intact.

“If you want to create a dexterous hand for use in an amputee or a quadriplegic patient, you need to not only be able to move it, but have sensory feedback from it,” said Bensmaia, who is an associate professor of organismal biology and anatomy at the University of Chicago. “To do this, we first need to look at how the intact hand and the intact nervous system encodes this information, and then, to the extent that we can, try to mimic that in a neuroprosthesis.”

Recreating different sensations of intensity

The latest research is a joint effort by Bensmaia and Dustin Tyler, PhD, the Kent H. Smith Professor of Biomedical Engineering at Case Western Reserve University, who works with a large team trying to make bionic hands clinically viable. Tyler’s team, led by doctoral student Emily Graczyk, systematically tested the subjects’ ability to distinguish the magnitude of the sensations evoked when their nerves were stimulated through the interface. They varied aspects of the signals, such as frequency and intensity of each electrical pulse. The goal was to understand if there was a systematic way to manipulate the sensory magnitude.

Earlier research from Bensmaia’s lab predicted how the nervous system discerns intensity of touch, for example, how hard an object is pressing against the skin. That work suggested that the number of times certain nerve fibers fire in response to a given stimulus, known as the population spike rate, determines the perceived intensity of a given stimulus.

Results from the new study verify this hypothesis: A single feature of electrical stimulation—dubbed the activation charge rate—was found to determine the strength of the sensation. By changing the activation charge rate, the team could change sensory magnitude in a highly predictable way. The team then showed that the activation charge rate was also closely related to the evoked population spike rate.

Building neuroprosthetics that approximate the natural nervous system

While the new study furthers the development of neural interfaces for neuroprosthetics, artificial touch will only be as good as the devices providing input. In a separate paper published earlier this year in IEEE Transactions on Haptics, Bensmaia and his team tested the sensory abilities of a robotic fingertip equipped with touch sensors.

Using the same behavioral techniques that are used to test human sensory abilities, Bensmaia’s team, led by Benoit Delhaye and Erik Schluter, tested the finger’s ability to distinguish different touch locations, different pressure levels, the direction and speed of surfaces moving across it and the identity of textures scanned across it. The robotic finger (with the help of machine learning algorithms) proved to be almost as good as a human at most of these sensory tasks. By combining such high-quality input with the algorithms and data Bensmaia and Tyler produced in the other study, researchers can begin building neuroprosthetics that approximate natural sensations of touch.

Without realistic, natural-feeling sensations, neuroprosthetics will never come close to achieving the dexterity of our native hands. To illustrate the importance of touch, Bensmaia referred to a piano. Playing the piano requires a delicate touch, and an accomplished pianist knows how softly or forcefully to strike the keys based on sensory signals from the fingertips. Without these signals, the sounds the piano would make would not be very musical.

“The idea is that if we can reproduce those signals exactly, the amputee won’t have to think about it, he can just interact with objects naturally and automatically. Results from this study constitute a first step towards conveying finely graded information about contact pressure,” Bensmaia said.

New Hope For Recovery Of Hand Movement For Stroke Patients

Stroke patients are starting a trial of a new electronic device to recover movement and control of their hand.

Neuroscientists at Newcastle University have developed the device, the size of a mobile phone, which delivers a series of small electrical shocks followed by an audible click to strengthen brain and spinal connections.

The experts believe this could revolutionise treatment for patients, providing a wearable solution to the effects of stroke.

Following successful work in primates and healthy human subjects, the Newcastle University team are now working with colleagues at the prestigious Institute of Neurosciences, Kolkata, India, to start the clinical trial. Involving 150 stroke patients, the aim of the study is to see whether it leads to improved hand and arm control.

Stuart Baker, Professor of Movement Neuroscience at Newcastle University who has led the work said: “We were astonished to find that a small electric shock and the sound of a click had the potential to change the brain’s connections. However, our previous research in primates changed our thinking about how we could activate these pathways, leading to our study in humans.”

Recovering hand control

Publishing today in the Journal of Neuroscience, the team report on the development of the miniaturised device and its success in healthy patients at strengthening connections in the reticulospinal tract, one of the signal pathways between the brain and spinal cord.

This is important for patients as when people have a stroke they often lose the major pathway found in all mammals connecting the brain to spinal cord. The team’s previous work in primates showed that after a stroke they can adapt and use a different, more primitive pathway, the reticulospinal tract, to recover.

However, their recovery tends to be imbalanced with more connections made to flexors, the muscles that close the hand, than extensors, those that open the hand. This imbalance is also seen in stroke patients as typically, even after a period of recuperation, they find that they still have weakness of the extensor muscles preventing them opening their fist which leads to the distinctive curled hand.

Partial paralysis of the arms, typically on just one side, is common after stroke, and can affect someone’s ability to wash, dress or feed themselves. Only about 15% of stroke patients spontaneously recover the use of their hand and arm, with many people left facing the rest of their lives with a severe level of disability.

Senior author of the paper, Professor Baker added: “We have developed a miniaturised device which delivers an audible click followed by a weak electric shock to the arm muscle to strengthen the brain’s connections. This means the stroke patients in the trial are wearing an earpiece and a pad on the arm, each linked by wires to the device so that the click and shock can be continually delivered to them.

“We think that if they wear this for 4 hours a day we will be able to see a permanent improvement in their extensor muscle connections which will help them gain control on their hand.”

Improving connections

The techniques to strengthen brain connections using paired stimuli are well documented, but until now this has needed bulky equipment, with a mains electric supply.

The research published today is a proof of concept in human subjects and comes directly out of the team’s work on primates. In the paper they report how they pair a click in a headphone with an electric shock to a muscle to induce the changes in connections either strengthening or weakening reflexes depending on the sequence selected. They demonstrated that wearing the portable electronic device for seven hours strengthened the signal pathway in more than half of the subjects (15 out of 25).

Professor Stuart Baker added: “We would never have thought of using audible clicks unless we had the recordings from primates to show us that this might work. Furthermore, it is our earlier work in primates which shows that the connections we are changing are definitely involved in stroke recovery.”

The work has been funded through a Milstein Award from the Medical Research Council and the Wellcome Trust.

The clinical trial is just starting at the Institute of Neurosciences, Kolkata, India. The country has a higher rate of stroke than Western countries which can affect people at a younger age meaning there is a large number of patients. The Institute has strong collaborative links with Newcastle University enabling a carefully controlled clinical trial with results expected at the end of this year.

Dysfunction In Neuronal Transport Mechanism Linked To Alzheimer’s Disease

Researchers at University of California San Diego School of Medicine have confirmed that mutation-caused dysfunction in a process cells use to transport molecules within the cell plays a previously suspected but underappreciated role in promoting the heritable form of Alzheimer’s disease (AD), but also one that might be remedied with existing therapeutic enzyme inhibitors.

The findings published in the October 11 online issue of Cell Reports.

“Our results further illuminate the complex processes involved in the degradation and decline of neurons, which is, of course, the essential characteristic and cause of AD,” said the study’s senior author Larry Goldstein, PhD, Distinguished Professor in the Departments of Neuroscience and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of both the UC San Diego Stem Cell Program and Sanford Stem Cell Clinical Center at UC San Diego Health. “But beyond that, they point to a new target and therapy for a condition that currently has no proven treatment or cure.”

Alzheimer’s disease is a neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction. It affects more than 30 million people worldwide, including an estimated 5.4 million Americans. One in 10 persons over the age of 65 has AD; one in three over the age of 85. There are currently no treatments proven to cure or reduce the progression of AD.

Genetically, AD is divided into two groups: the much more common sporadic (sAD) form of the disease in which the underlying primary cause is not known and the rarer familial (fAD) form, produced by inherited genetic mutations. In both forms, the brains of AD patients feature accumulations of protein plaques and neurofibrillary tangles that lead to neuronal impairment and eventual cell death.

The prevailing “amyloid cascade hypothesis” posits that these plaques and tangles are comprised, respectively, of amyloid precursor protein (APP) fragments and tau proteins that fuel cellular stress, neurotoxicity, loss of function and cell death. There has been some evidence, however, of another disease-driver: defects in endocytic trafficking — the process by which cells package large, external molecules into vesicles or membrane-bound sacs for transport into the cell for a variety of reasons or uses.

But previous research focused on non-neuronal cells and did not examine the effects of normal expression levels of AD-related proteins, leaving it unclear to what degree decreased endocytosis and other molecular movement within cells played a causative role.

Goldstein and colleagues analyzed neurons created from induced pluripotent stem cells in which they generated PS1 and APP mutations characteristic of fAD using the emerging genome editing technologies CRISPR and TALEN. In this “disease-in-a-dish” approach, they found that the mutated neurons displayed altered distribution and trafficking of APP and internalized lipoproteins (proteins that combine with or transport fat and other lipids in blood plasma). Specifically, there were elevated levels of APP in the soma or cell body while levels were reduced in the neuronal axons.

In previous work, Goldstein’s team had demonstrated that PS1 and APP mutations impaired the activity of specific cellular enzymes. In the latest work, they found that treating mutated fAD neurons with a beta-secretase inhibitor rescued both endocytosis and transcytosis (molecule movement within a cell) functions.

Glutamate Plays Previously Unknown Role In Neuromuscular Development

For decades, scientists thought acetylcholine was the only neurotransmitter responsible for controlling how muscles and nerves are wired together during development.

Turns out, they were wrong. Glutamate, the most common neurotransmitter in the brain, is also necessary.

Researchers at the University at Buffalo and Johns Hopkins University reported their findings with mice in the Journal of Neuroscience.

The team took a new approach to the old question of how the connections from the spinal cord to the muscles mature, says Kirkwood Personius, the paper’s lead author and a clinical associate professor of rehabilitation science in UB’s School of Public Health and Health Professions.

Each muscle is made of many individual muscle fibers and, in adults, each of those muscle fibers is contacted by a single motor neuron. However, this simple arrangement is not what you see at birth. Instead, each muscle fiber is contacted by as many as 10 nerves.

The process that allows one motor neuron to stay while all the others are retracted seems to be this, according to the researchers: the nerve that’s most effective in activating the muscle is the one that wins.

But what specifically occurs during the nerve’s firing that triggers the stabilizing of the winner and the withdrawal of the others? For many decades, it was assumed that the pruning process began with release of the neurotransmitter acetylcholine from the nerve. This seemed logical, the paper’s authors say, because motor neurons do indeed release lots of acetylcholine.

“However, we now have shown that an important transmitter is one that nobody had previously expected: it is glutamate,” said Personius, PT, PhD. “The nerves release a molecule that is converted into glutamate, and the glutamate then activates glutamate receptors, notably NMDA receptors, on the muscle.”

NMDA (N-methyl-D-aspartate) receptors are one of several types of molecules that respond to glutamate. They are especially important in the central nervous system controlling brain development, learning and synaptic plasticity. “Nobody thought NMDA receptors played any role in the innervation of muscle,” Personius said.

The researchers tested their hypothesis — that glutamate receptor activation modulates the development of the neuromuscular system — in several ways, each of which supported what they thought. In addition, they showed that the response of the muscle to glutamate is very strong at birth, but quickly disappears as mice mature.

“Our work restarts a field that was stuck because of the widespread conviction that the process depended on a single transmitter, acetylcholine,” said Susan Udin, PhD, a paper co-author and professor of physiology in UB’s Jacobs School of Medicine and Biomedical Sciences.

“This study opens up a wide range of experimental possibilities because so much is known from central nervous system studies about how NMDA receptors work. Our work opens up a possible understanding of why return of muscle function is often limited after peripheral nerve trauma.”

The same processes that control muscle fiber development tend to recur after peripheral injury in adults. Now, the research team is testing the hypothesis that the poor outcomes often seen after peripheral nerve trauma could be improved by manipulating NMDA receptors.

New Study Finds Connection Between Chronic Pain And Anxiety Disorders

New research provides insight into a long-observed, but little-understood connection between chronic pain and anxiety and offers a potential target for treatment. The study’s findings, published as an Article in Press in Biological Psychiatry, show that increased expression of PACAP – a peptide neurotransmitter the body releases in response to stress – is also increased in response to neuropathic pain and contributes to these symptoms.

The researchers examined the expression of PACAP (pituitary adenylate cyclase activating polypeptide) along one of the nervous system’s pathways to the brain – the spino-parabrachiomygdaloid tract – which travels from the spinal cord to the amygdala, the brain’s home base for emotional behavior.

Using models for chronic pain and anxiety, as well as models that can trace PACAP neurocircuits, the team members were able to observe where the stress and chronic pain pathways intersected.

“Chronic pain and anxiety-related disorders frequently go hand-in-hand,” says senior author Victor May, Ph.D., professor of neurological sciences at the University of Vermont. In a 2011 study, he and members of the research team found that PACAP was highly expressed in women exhibiting PTSD symptoms.

While May and his colleagues saw an increase in anxiety-related behaviors in models of chronic pain, the anxious behavior and pain hypersensitivity were significantly reduced when a PACAP receptor antagonist – designed to block the response – was applied.

“By targeting this regulator and pathway, we have opportunities to block both chronic pain and anxiety disorders,” says May, whose next step is to work with University of Vermont chemistry colleagues to develop small molecule compounds that can antagonize PACAP actions. “This would be a completely different approach to using benzodiazepine and opioids – it’s another tool in the arsenal to battle chronic pain and stress-related behavioral disorders.”

George Washington University Researchers Receive $1.6 Million to Improve Cardiac Function During Heart Failure

Researchers at the George Washington University (GW) received $1.6 million from the National Heart, Lung, and Blood Institute to study a heart-brain connection that could help the nearly 23 million people suffering from heart failure worldwide. The four-year project will study ways to restore parasympathetic activity to the heart through oxytocin neuron activation, which could improve cardiac function during heart failure.

A distinctive hallmark of heart failure is autonomic imbalance, consisting of increased sympathetic activity and decreased parasympathetic activity. Parasympathetic activity is cardiac protective.

“Parasympathetic activity is what you have when you’re reading a book, or relaxing, and counteracts the sympathetic activity you have when you’re stuck on the metro or have an exam tomorrow,” said David Mendelowitz, Ph.D., vice chair and professor in the Department of Pharmacology and Physiology at the GW School of Medicine and Health Sciences. “Heart failure is a disease that effects both neuro and cardiac function.”

Unfortunately, few effective treatments exist to increase parasympathetic activity to the heart. Based upon exciting preliminary results, this study will examine the activation of neurons in the hypothalamus that release oxytocin, which has shown to increase parasympathetic activity in the heart. While oxytocin is often used to start or increase speed of labor, recent research has uncovered its role in feelings of generosity and bonding. It may also have beneficial effects on the heart.

The project is a collaboration between the GW School of Medicine and Health Sciences and the GW School of Engineering and Applied Science.

“While Dr. Mendelowitz’s research is focused on neuroscience and how the brain works, my work is focused on cardiac function. Heart failure is a disease that affects both, which is why it is imperative for Dr. Mendelowitz and I to use our complimentary expertise to solve this problem,” said Matthew Kay, PE, DSc, associate professor in the Department of Biomedical Engineering at the GW School of Engineering and Applied Science.

Kay and his research team will use high-speed optical assessments of heart function to identify heart-specific benefits of oxytocin nerve activation. Working together, Mendelowitz and Kay have the potential to unravel the complex interaction between the brain and the heart during heart failure.

Brain Cells That Aid Appetite Control Identified

It’s rare for scientists to get what they describe as “clean” results without spending a lot of time repeating the same experiment over and over again. But when researchers saw the mice they were working with doubling their weight within a month or two, they knew they were on to something.

“About twenty years ago there was a big step forward in our understanding of obesity when researchers discovered that our appetite is controlled by a key molecule called leptin. Leptin is a hormone which is produced by our fat cells, and is delivered by the blood to the brain to signal the brain that we are full and can stop eating,” explains Dr. Maia Kokoeva who is affiliated both with McGill University and the Research Institute of the McGill University Health Centre. “But even though receptors for leptin were discovered soon after in the hypothalamus, a brain area that regulates food intake and body weight, it has remained unclear how exactly leptin is detected.”

So about four years ago, Kokoeva and her team set out to explore which brain cells might play a role in the process of leptin sensing and weight gain. The answer, it turns out, lies in the median eminence.

“Protection” and “preservation” cells in a busy place
The median eminence is a brain structure at the base of the hypothalamus. It is a bit like a busy hub or market place through which hormones and molecules of various kinds travel in both directions between the brain and the bloodstream to ensure that the body functions smoothly.

The McGill research team has now discovered that without a particular group of cells (known as NG2-glia cells) in place in the median eminence, the leptin receptors in the brain never receive the messages from the body telling it that it is sated.

“Most of the brain is a well-protected fortress, designed to shelter delicate nerve cells,” says Kokoeva. “The median eminence is outside these protections, and so can be a dangerous environment for the nerve cells that detect leptin. We think that the NG2-glia cells act to support and shelter the leptin receptor neurons, enabling them to instruct the body when to stop eating.”

Crucial role of the median eminence in weight gain
“We developed an interest in NG2-glia cells in this specific part of the brain because unlike neurons, during much of our adult lives these cells are constantly dividing and they do so most actively in the median eminence,” says Tina Djogo, a McGill doctoral student and one of two lead authors on the study which was published this week in Cell Metabolism. “But though these cells were first described about thirty years ago it has been difficult so far to pinpoint their exact functions in the adult brain.”

Because of their particularly high turnover in the median eminence, the researchers wondered if the NG2-glia cells might play a role in leptin sensing and therefore in appetite control. So they used a drug to kill the NG2-glia cells in the median eminence of a group of mice and then watched to see whether there was a difference in food intake. The results were stunning.

Within three days after they started to receive the medication, some of the mice dubbed “gainers” had already started to eat more compared with the control group of mice who had not received medication. And by 30 days afterwards, the weight of some of the mice had doubled – from 25 grams to around 50 grams.

“But what was most exciting to us, was that even though NG2-glia are found across the brain” explains Sarah Robins, a research associate who was also a lead author on this study, “it was only when we removed these cells from the median eminence that we saw this clear increase in body weight.”

A possible explanation for weight gain in brain tumour patients
The researchers then corroborated the role of the NG2-glia cells in the median eminence in appetite control through experiments using genetically modified mice, and also by using irradiation. This latter discovery suggested an explanation for a previously unexplained phenomenon in human brain cancer survivors.

“People who have been treated for brain tumours using radiation to block cell proliferation often become overweight,” says Kokoeva. “However, there has never been any satisfactory explanation, but our experiments in mice now suggests that the reason for this weight gain may be the loss of NG2-glia in the median eminence as a result of radiation.”

The researchers are hopeful that the identification of NG2-glia in the median eminence as crucial elements in body weight and appetite control will pave the way to new targeted anti-obesity approaches directed towards maintaining or raising the NG2-glia population in the median eminence.