Peptides helping researchers in search for Parkinson’s disease treatment

Australian researchers have taken the first step in using bioactive peptides as the building blocks to help ‘build a new brain’ to treat degenerative brain disease.

Deakin University biomedical scientist Dr Richard Williams is working in a team with Dr David Nisbet from the Australian National University and Dr Clare Parish at the Florey Neuroscience Institute to develop a way to repair the damaged parts of the brain that cause Parkinson’s disease.

Parkinson’s disease develops when the brain cells (or neurons) that produce the chemical dopamine die or are damaged. Dopamine neurons produce a lubricant that helps the brain transmit signals to the body that control muscles and movement. When these cells die or are damaged the result is the shaking and muscle stiffness that are among the common symptoms of the disease.

"We are looking at a way of helping the brain to regenerate the dead or damaged cells that transport dopamine throughout the body," Dr Williams said. "Peptides help the body heal itself, providing many positive benefits for health, particularly in regenerative medicine; this is why the sports people were using them to recover more quickly in the current doping scandal."

Peptides are both the building blocks and the messengers of the body; the team has used them to mimic the normal brain environment and provide the chemical signals needed to help the brain function.

"Peptides stick together like Lego blocks, so in the first stage of the project we have been able to make a three dimensional material or tissue scaffold that provides the networks cells need to grow; but the peptides also carry instructions in the form of chemical signals which tell the cells to grow into new neurons," Dr Williams explained.

"Importantly, this material has the same consistency as the brain, does not cause chronic inflammation and is non-toxic to the body.

"Our aim is to use this scaffold material to support the patient’s own stem cells that could be turned into dopamine neurons and implanted back into the brain. We expect that when implanted the material and stem cells would be accepted by the brain as normal tissue and grow to replace the damaged or dead cells."

While the research is not yet complete, Dr Williams is excited by the possibilities this work offers to the treatment of degenerative conditions.

"It is no secret that we are living longer, and with this we are seeing an increase in many conditions that come about because of ageing such Parkinson’s. By developing biomaterials, like the ones we are working on, it could be possible to help the body to regenerate and provide an improved quality of life to the older members of our community," he said.

"This work can also be adapted to other parts of the body which struggle to repair themselves, such as new cartilage for joints, muscle and heart cells, bones and teeth. Ultimately, it will be like taking your car to the garage to have new parts fitted to replace the worn out ones."

The results of the first stage of this Australian Research Council funded project will be published in the international journal Soft Matter.

Study indicates reverse impulses clear useless information, prime brain for learning

When the mind is at rest, the electrical signals by which brain cells communicate appear to travel in reverse, wiping out unimportant information in the process, but sensitizing the cells for future sensory learning, according to a study of rats conducted by researchers at the National Institutes of Health.

The finding has implications not only for studies seeking to help people learn more efficiently, but also for attempts to understand and treat post-traumatic stress disorder—in which the mind has difficulty moving beyond a disturbing experience.

During waking hours, brain cells, or neurons, communicate via high-speed electrical signals that travel the length of the cell. These communications are the foundation for learning. As learning progresses, these signals travel across groups of neurons with increasing rapidity, forming circuits that work together to recall a memory.

It was previously known that, during sleep, these impulses were reversed, arising from waves of electrical activity originating deep within the brain. In the current study, the researchers found that these reverse signals weakened circuits formed during waking hours, apparently so that unimportant information could be erased from the brain. But the reverse signals also appeared to prime the brain to relearn at least some of the forgotten information. If the animals encountered the same information upon awakening, the circuits re-formed much more rapidly than when they originally encountered the information.

"The brain doesn’t store all the information it encounters, so there must be a mechanism for discarding what isn’t important," said senior author R. Douglas Fields, Ph.D., head of the Section on Nervous System Development and Plasticity at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute where the research was conducted. "These reverse brain signals appear to be the mechanism by which the brain clears itself of unimportant information."

Their findings appear in the Proceedings of the National Academy of Sciences.

The researchers studied the activity of rats’ brain cells from the hippocampus, a tube-like structure deep in the brain. The hippocampus relays information to and from many other regions of the brain. It plays an important role in memory, orientation, and navigation.

The classic understanding of brain cell activity is that electrical signals travel from dendrites—antenna-like projections at one end of the cell—through the cell body. From the cell body, they then travel the length of the axon, a single long projection at the other end of the cell. This electrical signal stimulates the release of chemicals at the end of the axon, which bind to dendrites on adjacent cells, stimulating these recipient cells to fire electrical signals, and so on. When groups of cells repeatedly fire in this way, the electrical signals increase in intensity.

Dr. Bukalo and her team examined electrical signals that traveled in reverse—from the cell’s axon, to the cell body, and out its many dendrites. This reverse firing happens during sleep and at rest, appearing to reset the cell, the researchers found.

After first stimulating the cells with reverse electrical impulses, the researchers next stimulated the dendrites again with electrical impulses traveling in the forward direction. In response, the neurons generated a stronger signal, with the connections appearing to strengthen with repeated electrical stimulation.

This pattern appears to underlie the formation of new memories. A connection that is reset but never stimulated again may simply fade from use over time, Dr. Bukalo explained. But when a cell is stimulated again, it fires a stronger signal and may be more easily synchronized to the reinforced signals of other brain cells, all of which act in concert over time.

Depression stems from miscommunication between brain cells

A new study from the University of Maryland School of Medicine suggests that depression results from a disturbance in the ability of brain cells to communicate with each other. The study indicates a major shift in our understanding of how depression is caused and how it should be treated. Instead of focusing on the levels of hormone-like chemicals in the brain, such as serotonin, the scientists found that the transmission of excitatory signals between cells becomes abnormal in depression. The research, by senior author Scott M. Thompson, Ph.D., Professor and Interim Chair of the Department of Physiology at the University of Maryland School of Medicine, was published online in the March 17 issue of Nature Neuroscience.

"Dr. Thompson’s groundbreaking research could alter the field of psychiatric medicine, changing how we understand the crippling public health problem of depression and other mental illness," says E. Albert Reece, M.D., Ph.D., M.B.A., Vice President for Medical Affairs at the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor and Dean at the University of Maryland School of Medicine. "This is the type of cutting-edge science that we strive toward at the University of Maryland, where discoveries made in the laboratory can impact the clinical practice of medicine."

The first major finding of the study was the discovery that serotonin has a previously unknown ability to strengthen the communication between brain cells. “Like speaking louder to your companion at a noisy cocktail party, serotonin amplifies excitatory interactions in brain regions important for emotional and cognitive function and apparently helps to make sure that crucial conversations between neurons get heard,” says Dr. Thompson. “Then we asked, does this action of serotonin play any role in the therapeutic action of drugs like Prozac?”

To understand what might be wrong in the brains of patients with depression and how elevating serotonin might relieve their symptoms, the study team examined the brains of rats and mice that had been repeatedly exposed to various mildly stressful conditions, comparable to the types of psychological stressors that can trigger depression in people.

The researchers could tell that their animals became depressed because they lost their preference for things that are normally pleasurable. For example, normal animals given a choice of drinking plain water or sugar water strongly prefer the sugary solution. Study animals exposed to repeated stress, however, lost their preference for the sugar water, indicating that they no longer found it rewarding. This depression-like behavior strongly mimics one hallmark of human depression, called anhedonia, in which patients no longer feel rewarded by the pleasures of a nice meal or a good movie, the love of their friends and family, and countless other daily interactions.

A comparison of the activity of the animals’ brain cells in normal and stressed rats revealed that stress had no effect on the levels of serotonin in the ‘depressed’ brains. Instead, it was the excitatory connections that responded to serotonin in strikingly different manner. These changes could be reversed by treating the stressed animals with antidepressants until their normal behavior was restored.

"In the depressed brain, serotonin appears to be trying hard to amplify that cocktail party conversation, but the message still doesn’t get through," says Dr. Thompson. Using specially engineered mice created by collaborators at Johns Hopkins University School of Medicine, the study also revealed that the ability of serotonin to strengthen excitatory connections was required for drugs like antidepressants to work.

Sustained enhancement of communication between brain cells is considered one of the major processes underlying memory and learning. The team’s observations that excitatory brain cell function is altered in models of depression could explain why people with depression often have difficulty concentrating, remembering details, or making decisions. Additionally, the findings suggest that the search for new and better antidepressant compounds should be shifted from drugs that elevate serotonin to drugs that strengthen excitatory connections.

"Although more work is needed, we believe that a malfunction of excitatory connections is fundamental to the origins of depression and that restoring normal communication in the brain, something that serotonin apparently does in successfully treated patients, is critical to relieving the symptoms of this devastating disease," Dr. Thompson explains.

(Image: McGovern Institute, MIT)

Some brain cells are better virus fighters

Viruses often spread through the brain in patchwork patterns, infecting some cells but missing others. New research at Washington University School of Medicine in St. Louis helps explain why. The scientists showed that natural immune defenses that resist viral infection are turned on in some brain cells but switched off in others.

“The cells that a pathogen infects can be a major determinant of the seriousness of brain infections,” says senior author Michael Diamond, MD, PhD, professor of medicine. “To understand the basis of disease, it is important to understand which brain regions are more susceptible and why.”

While some brain infections are caused by bacteria, fungi or parasites, often the cause is a virus, such as West Nile virus, herpesvirus or enteroviruses.

For their study, now available online in Nature Medicine, the researchers focused on granule cell neurons, a cell type that rarely becomes infected. They compared gene profiles in granule cells from the cerebellum with the activity in cortical neurons in the cerebral cortex, which are more vulnerable to infection.

The comparison revealed many differences, including a number of genes in cortical neurons that were less well-expressed—meaning that for those specific genes there were fewer copies of mRNA, the molecules that relay genetic information from DNA to the cell’s protein-making mechanisms.

Next, the researchers transferred individually 40 of those genes into cortical neurons and screened the cells for susceptibility to viral infection. The test highlighted three antiviral genes that are induced by interferon, an important immune system protein. When the expression level of these genes increased in cortical neurons, the cells’ susceptibility to viral infection decreased.

The researchers also identified mechanisms that make some of these changes in genetic programming happen: regulatory factors known as microRNA, and differences in the way DNA is modified in the cell nucleus, both of which can affect gene expression levels.

Some of the genetic changes are only helpful against specific viral families, while others are effective against a broader spectrum of viruses and bacteria. The scientists can’t say yet if the differences in infection susceptibility are driven by the need to prevent infection or if they are a byproduct of changes that help neurons in particular brain regions perform essential functions.

To learn more about how these innate immune genes help cells resist infection, Diamond and his colleagues are disabling them in the brains of mice.

Even mild traumatic brain injuries can kill brain tissue

Scientists have watched a mild traumatic brain injury play out in the living brain, prompting swelling that reduces blood flow and connections between neurons to die.

“Even with a mild trauma, we found we still have these ischemic blood vessels and, if blood flow is not returned to normal, synapses start to die,” said Dr. Sergei Kirov, neuroscientist and Director of the Human Brain Lab at the Medical College of Georgia at Georgia Regents University.

They also found that subsequent waves of depolarization – when brain cells lose their normal positive and negative charge – quickly and dramatically increase the losses.

Researchers hope the increased understanding of this secondary damage in the hours following an injury will point toward better therapy for the 1.7 million Americans annually experiencing traumatic brain injuries from falls, automobile accidents, sports, combat and the like.  While strategies can minimize impact, no true neuroprotective drugs exist, likely because of inadequate understanding about how damage unfolds after the immediate impact.

Kirov is corresponding author of a study in the journal Brain describing the use of two-photon laser scanning microscopy to provide real-time viewing of submicroscopic neurons, their branches and more at the time of impact and in the following hours.

Scientists watched as astrocytes – smaller cells that supply neurons with nutrients and help maintain normal electrical activity and blood flow – in the vicinity of the injury swelled quickly and significantly. Each neuron is surrounded by several astrocytes that ballooned up about 25 percent, smothering the neurons and connective branches they once supported.

“We saw every branch, every small wire and how it gets cut,” Kirov said. “We saw how it destroys networks. It really goes downhill. It’s the first time we know of that someone has watched this type of minor injury play out over the course of 24 hours.”

Stressed neurons ran out of energy and became silent but could still survive for hours, potentially giving physicians time to intervene, unless depolarization follows. Without sufficient oxygen and energy, internal pumps that ensure proper polarity by removing sodium and pulling potassium into neurons, can stop working and dramatically accelerate brain-cell death.

“Like the plus and minus ends of a battery, neurons must have a negative charge inside and a positive charge outside to fire,” Kirov said. Firing enables communication, including the release of chemical messengers called neurotransmitters.

“If you have six hours to save tissue when you have just lost part of your blood flow, with this spreading depolarization, you lose tissue within minutes,” he said.

While common in head trauma, spreading depolarization would not typically occur in less-traumatic injuries, like his model. His model was chemically induced to reveal more about how this collateral damage occurs and whether neurons could still be saved. Interestingly, researchers found that without the initial injury, brain cells completely recovered after re-polarization but only partially recovered in the injury model.

While very brief episodes of depolarization occur as part of the healthy firing of neurons, spreading depolarization exacerbates the initial traumatic brain injury in more than half of patients and results in poor prognosis, previous research has shown. However, a 2011 review in the journal Nature Medicine indicated that short-lived waves can actually protect surrounding brain tissue. Kirov and his colleagues wrote that more study is needed to determine when to intervene.

One of Kirov’s many next steps is exploring the controversy about whether astrocytes’ swelling in response to physical trauma is a protective response or puts the cells in destruct mode. He also wants to explore better ways to protect the brain from the growing damage that can follow even a slight head injury.

Currently, drugs such as diuretics and anti-seizure medication may be used to help reduce secondary damage of traumatic brain injury. Astrocytes can survive without neurons but the opposite is not true, Kirov said. The ratio of astrocytes to neurons is higher in humans and human astrocytes are more complex, Kirov said.

How the Body’s Energy Molecule Transmits Three Types of Taste to the Brain

Saying that the sense of taste is complicated is an understatement, that it is little understood, even more so. Exactly how cells transmit taste information to the brain for three out of the five primary taste types was pretty much a mystery, until now.

A team of investigators from nine institutions discovered how ATP – the body’s main fuel source – is released as the neurotransmitter from sweet, bitter, and umami, or savory, taste bud cells. The CALHM1 channel protein, which spans a taste bud cell’s outer membrane to allow ions and molecules in and out, releases ATP to make a neural taste connection. The other two taste types, sour and salt, use different mechanisms to send taste information to the brain.

Kevin Foskett, PhD, professor of Physiology at the Perelman School of Medicine, University of Pennsylvania, and colleagues from the Monell Chemical Senses Center, the Feinstein Institute for Medical Research, and others, describe in Nature how ATP release is key to this sensory information path. They found that the calcium homeostasis modulator 1 (CALHM1) protein, recently identified by the Foskett lab as a novel ion channel, is indispensable for taste via release of ATP.  

“This is an example of a bona fide ATP ion channel with a clear physiological function,” says Foskett. “Now we can connect the molecular dots of sweet and other tastes to the brain.”

Taste buds have specialized cells that express G-protein coupled receptors (GPCRs) that bind to taste molecules and initiate a complex chain of molecular events, the final step of which Foskett and collaborators show is the opening of a pore in the cell membrane formed by CALHM1. ATP molecules leave the cell through this pore to alert nearby neurons to continue the signal to the taste centers of the brain. CALHM1 is expressed specifically in sweet, bitter, and umami taste bud cells.

Mice in which CALHM1 proteins are absent, developed by Feinstein’s Philippe Marambaud, PhD, have severely impaired perceptions of sweet, bitter and umami compounds; whereas, their recognition of sour and salty tastes remains mostly normal. The CALHM1 deficiency affects taste perception without interfering with taste cell development or overall function.

Using the CALHM1 knockout mice, team members from Monell and Feinstein tested how their taste was affected. “The mice are very unusual,” says Monell’s Michael Tordoff, PhD. “Control mice, like humans, lick avidly for sucrose and other sweeteners, and avoid bitter compounds. However, the mice without CALHM1 treat sweeteners and bitter compounds as if they were water. They can’t taste them at all.”

From all lines of evidence, the team concluded that CALHM1 is an ATP-release channel required for sweet, bitter, and umami taste perception. In addition, they found that CALHM1 was also required for  “nontraditional” Polycose, calcium, and aversive high-salt tastes, implying that the deficit displayed in the knockout animals might best be considered as a loss of all GPCR-mediated taste signals rather than simply sweet, bitter and umami taste.

Interestingly, CALHM1 was originally implicated in Alzheimer’s disease, although the link is now less clear. In 2008, co-author Marambaud identified CALHM1 as a risk gene for Alzheimer’s. They discovered that a CALHM1 genetic variant was more common among people with Alzheimer’s and they went on to show that it leads to a partial loss of function. They also found that this novel ion channel is strongly expressed in the hippocampus, a brain region necessary for learning and memory. So far, there is no connection between taste perception and Alzheimer’s risk, but Marambaud suspects that scientists will start testing this hypothesis.

Novel storage mechanism allows command, control of memory

Introductions at a party seemingly go in one ear and out the other. However, if you meet someone two or three times during the party, you are more likely to remember his or her name. Your brain has taken a short-term memory - the introduction - and converted it into a long-term one. The molecular key to this activity is mTORC2 (mammalian target of rapamycin complex 2), according to researchers at Baylor College of Medicine in an article that appeared online in the journal Nature Neuroscience.

"Memory consolidation is a fundamental process," said Dr. Mauro Costa-Mattioli, assistant professor of neuroscience at BCM and corresponding author of the report. "Memories are at the center of our identity. They allow us to remember people, places and events for a long time, even a lifetime. Understanding the precise mechanism by which memories are stored in the brain will lead to the development of new treatments for conditions associated with memory loss".

Actin fibers

For the last five decades, neuroscientists have known that making long-lasting memories is dependent on the ability of brain cells (neurons) to synthesize new proteins. In their studies, Costa-Mattioli and his colleagues found a new mechanism by which memories are stored in the brain. The newly discovered mTORC2 regulates memory formation by modulating actin fibers, an important component of the architectural structure of the neuron.

"These actin fibers allow long-lasting changes in synaptic strength and ultimately long-term memories," said Wei Huang, a BCM graduate student and first author in the study.

Using genetically-engineered mice, the researchers found that turning off mTORC2 in the hippocampus (a crucial region required for memory formation) and surrounding areas allowed the animals to have a normal short-term memory, but prevented them from forming long-term memories. Similar to human patients with injury in the hippocampus, these mutant mice were no longer able to form new long-lasting memories.

According to Costa-Mattioli’s findings, mTORC2’s role is evolutionarily conserved and likely relevant to humans. Like mTORC2-deficient mice, fruit flies lacking TORC2 show defective long-term memory storage.

"Given that flies and mice last shared a common ancestor 500 million years ago, it is quite remarkable and telling that the function of mTORC2 in the regulation of memory is indeed maintained," said Dr. Gregg Roman, director of the Biology of Behavior Institute at the University of Houston, who contributed to the fly experiments.

Form long-term memories

The Holy Grail of memory neuroscience and to a certain extent, of industry efforts to produce a “smart drug,” has been the identification of molecules that promote the formation of long-term memory, said Costa-Mattioli. “We therefore wondered whether by turning on mTORC2 or even actin polymerization itself, we could form long-term memories more easily,” said Dr. Ping Jun Zhu, assistant professor of neuroscience at BCM, co-first author and senior scientist in Costa-Mattioli’s lab.

The team has identified a small molecule (a drug) that by activating mTORC2 and consequently actin polymerization enhances not only the synaptic strength between nerve cells but also long-term memory formation. In addition, the authors found that by directly promoting actin polymerization, with a second drug, long-term memory is generated more easily.

Costa-Mattioli’s team has identified two memory-enhancing drugs, but can they enhance memory in people? It is perhaps too early to say.

Huang said, “mTORC2, as far as we know, is really a new potential target for therapeutic treatments of human disorders. In the next few years, I predict we will see a lot of studies focusing on mTORC2 as a target.”

Memory cocktail

Costa-Mattioli’s short-term goals are to identify human cognitive disorders in which mTORC2 activity is dysfunctional and to see whether its restoration can return to normal impaired memory function in aging or even Alzheimer’s disease. But a small molecule alone might not do the job. Similar to the treatments for HIV or cancer, he believes that a combination of small molecules improving different aspects of memory formation will be required to efficiently treat cognitive disorders.

"We should start thinking about an efficient ‘memory cocktail’ rather than a single ‘memory pill.’ One molecule alone might not be enough. We may be years away from a decisive treatment, but I believe we are definitely on the right path," he said.

Others who took part in this work include Hongyi Zhou, Loredana Stoica and Mauricio Galiano, all of BCM, Krešimir Krnjević of McGill University in Montreal, Canada; and Shixing Zhang of the University of Houston.

(Image: Shutterstock)