Posts tagged neuroscience
Articles and news from the latest research reports.
New headway in battle against neurodegenerative diseases
Conditions which may accelerate the spread of Parkinson’s disease, and a potential means of enhancing naturally-occurring defences against neurodegenerative disorders, have been identified in two new studies.
Two significant breakthroughs which could inform future treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s, have been announced by scientists.
The research, published in two separate studies this week, advances understanding of the early development of such disorders and how they might be prevented – in particular by identifying the biological areas and processes that could be pinpointed by future drugs.
Both sets of results have emerged from collaborations between the research groups led by Chris Dobson, Tuomas Knowles and Michele Vendruscolo at the University of Cambridge, who focus on understanding protein “misfolding” diseases. These include Alzheimer’s and Parkinson’s diseases, as well as numerous others.
The first study provides evidence that the early spread of the protein aggregates associated with Parkinson’s appears to happen at an accelerated rate in mildly acidic conditions. This suggests that particular compartments within brain cells, which are slightly more acidic than others, may turn out to be appropriate targets for future treatments fighting the disease.
Meanwhile, researchers behind the second study appear to have identified a way in which the effectiveness of so-called molecular “chaperones”, responsible for limiting the damage caused by misfolded proteins, can be significantly enhanced.
The papers appear in the latest issue of Proceedings of the National Academy of Sciences of the USA.
As the term suggests, protein misfolding diseases stem from the fact that proteins, which need to fold into a particular shape to carry out their assigned function in the body, can sometimes misfold. In certain cases these misfolded proteins then clump together into fibre-like threads, called amyloid fibrils, potentially becoming toxic to other cells.
How this formation begins at a molecular level is still not completely understood, but comprehending the process will be fundamental to the development of future therapies and is the subject of extensive current research.
The first of the new studies builds on research published in 2013, which showed that in Alzheimer’s sufferers, the initial “nucleation” between proteins, which leads to amyloid formation, is followed by an amplification process called secondary nucleation. In these secondary events, the existing amyloid structures facilitate the formation of new aggregates, leading to their exponential increase. This process is likely to be at the heart of the development and spread of the disease in affected brains.
Using the same techniques, the researchers behind the latest study identified a similar process that is relevant in the early stage development of Parkinson’s Disease. Their work focused on a protein called α-synuclein, which is associated with the disorder, and simulated different conditions in which this protein might misfold and form clumps.
As with the previous study on Alzheimer’s, the research identified that Parkinson’s could spread through a series of secondary nucleation events. In addition, however, it showed that in the case of α-synuclein, this happens at a highly accelerated rate only in solutions which are mildly acidic, with a pH below 5.8. The finding is important because certain sub-compartments within cells are more acidic than others, meaning that these may be particularly productive areas for future treatments to target.
Dr Tuomas Knowles, from the Department of Chemistry and a Fellow of St John’s College, Cambridge, said: “This tells us much more about the molecular mechanisms underlying protein aggregation in Parkinson’s and suggests that mildly acidic microenvironments within cells may enhance that process by several orders of magnitude. Not every sub-cellular compartment offers these conditions, so it takes us much closer to understanding how the disease might spread.”
The second study meanwhile suggests a potential route to improving the effectiveness of a particular molecular “chaperone” – a loose classification for proteins which assist in the folding of others, thereby preventing them from causing damage when they misfold.
The researchers focused on a chaperone called α2-macroglobulin (α2M), which is found outside cells themselves. This is important because neurodegenerative diseases often stem from a process which begins with extracellular misfolding. The α2M was tested on a substrate of the amyloid-beta peptide associated with Alzheimer’s Disease.
Typically, the potency of α2M is limited. The new study, however, found that when it comes into contact with the oxidant hypochlorite – the same chemical found in household bleach, which also naturally occurs in our immune systems – its structure is modified in a manner that makes it into a much more dynamic defence.
In their report, the researchers suggest that this increased effectiveness stems from the fact that α2M, which is usually found in a four-part, “tetrameric” form, breaks down into “dimeric”, two-part forms when it comes into contact with hypochlorite.
The chaperone usually plays its role by preventing a misfolded protein from interacting with the membranes that surround and protect cells. Once in its dimeric form, however, receptor binding sites within the α2M are exposed, leading to specific interactions with receptors on the cell itself. If the α2M has already interacted with misfolded proteins, this connection triggers the cell to break the potentially harmful protein down.
“It’s almost like a warning flag for the cell, telling it that something is wrong,” Dr Janet Kumita, from the Department of Chemistry, explained. “It triggers the cell to react in a way that subjects the cargo of misfolded protein to a degradation pathway.”
“Increasing its potency in this way is an exciting prospect. If we could find a way of developing a drug that introduces the same structural alterations, we would have a therapeutic intervention capable of increasing this protective activity in patients with Alzheimer’s Disease.”
Professor Christopher Dobson, from the University’s Department of Chemistry and Master of St John’s College, said: “These studies add very substantially to our detailed understanding of the molecular origins of neurodegenerative diseases, which are now becoming one of the greatest threats to healthcare in the modern world.”
“We are beginning to understand exactly how a single, aberrant event can lead to the proliferation and spreading of toxic species throughout the brain, and the manner in which our sophisticated defence mechanisms do their best to suppress such phenomena. It will undoubtedly provide vital clues to the development in due course of new and effective drugs to combat these debilitating and increasingly common disorders.”
Brain’s response to sexual images linked to number of sexual partners
Like most things, sex requires motivation. An attractive face, a pleasant fragrance, perhaps a sexy image. Yet people differ in their response to sex cues, some react strongly; some don’t. A greater responsiveness to sexual cues might provide greater motivation for a person to act sexually, and risky sexual behaviors typically occur when a person is motivated by particularly potent, sexual reward cues.
Now researchers at UCLA have, for the first time, directly linked brain responses and real-world sexual behaviors. Specifically, the researchers found that how strongly the brain responded to viewing such images was related to the number of sex partners a person had in the previous year.
Led by Nicole Prause, a research scientist in the department of psychiatry in the UCLA Semel Institute for Neuroscience and Human Behavior, the study was published in the current online edition of the journal Social Cognitive and Affective Neuroscience. Prause and her colleagues used electroencephalogram (EEG) to measure a particular type of electrical activity in the brains of people as they were viewing a variety of images — some romantic, some pornographic, and some having nothing at all to do with sex.
Understanding how the brain responds to sexual images could help scientists create a brain stimulation intervention to reduce sensitivity to sexual reward and thus reduce some people’s proclivity to engage in risky sexual activities.
"These are the first data we know of that link brain responses to actual sexual risk behaviors," said Prause, who directs the Sexual Psychophysiology and Affective Neuroscience Laboratory at UCLA. "If your brain responds very strongly even to very tame pictures of sex, then you seem to be easily sexually excited in the real world, too. If we show very explicit sex pictures, eventually everyone’s brain responds strongly. It is those weaker images, just hinting at sex, that show the difference."
In the study, 40 men and 22 women, ages 18 to 40, completed a questionnaire that included the question, “How many partners have you had sexual intercourse with in the last 12 months?” They then were shown 225 images that included non-sexual, pleasant images (for example, skydiving), neutral images (like portraits) and sexual images ranging from G-rated to explicit scenes.
While viewing the images, participants’ brain activity was measured by EEG. Specifically, the researchers looked at a type of activity called late positive potential, which reacts to images depending on their emotional intensity.
The researchers found that participants who reported having had a higher number of sexual partners in the previous year exhibited similar late positive potential responses to both the graphic and less-graphic sexual images. Those who reported having had fewer intercourse partners in the previous year were different: They showed reduced late positive potential responses to the less explicit sexual images and greater response to the more graphic images.
"This pattern helps tell us why people may choose to pursue new sex partners," Prause said. "For example, some researchers have suggested that people may pursue new partners to experience sexual excitement that they did not experience in their regular lives or with their regular partner. These results, she said, "suggest that new partners actually might be pursued because people have high sexual excitement in response to any potential partner, whether regular or new. This distinction is very important if we want to help people feel in control of their sexual urges."
Stem Cell Therapy Shows Promise for MS in Mouse Model
Mice crippled by an autoimmune disease similar to multiple sclerosis (MS) regained the ability to walk and run after a team of researchers led by scientists at The Scripps Research Institute (TSRI), University of Utah and University of California (UC), Irvine implanted human stem cells into their injured spinal cords.
Remarkably, the mice recovered even after their bodies rejected the human stem cells. “When we implanted the human cells into mice that were paralyzed, they got up and started walking a couple of weeks later, and they completely recovered over the next several months,” said study co-leader Jeanne Loring, a professor of developmental neurobiology at TSRI.
Thomas Lane, an immunologist at the University of Utah who co-led the study with Loring, said he had never seen anything like it. “We’ve been studying mouse stem cells for a long time, but we never saw the clinical improvement that occurred with the human cells that Dr. Loring’s lab provided,” said Lane, who began the study at UC Irvine.
The mice’s dramatic recovery, which is reported online ahead of print by the journal Stem Cell Reports, could lead to new ways to treat multiple sclerosis in humans.
"This is a great step forward in the development of new therapies for stopping disease progression and promoting repair for MS patients,” said co-author Craig Walsh, a UC Irvine immunologist.
Stem Cell Therapy for MS
MS is an autoimmune disease of the brain and spinal cord that affects more than a half-million people in North America and Europe, and more than two million worldwide. In MS, immune cells known as T cells invade the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating on nerve fibers called myelin. Affected nerve fibers lose their ability to transmit electrical signals efficiently, and this can eventually lead to symptoms such as limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression.
Current therapies, such as interferon beta, aim to suppress the immune attack that strips the myelin from nerve fibers. But they are only partially effective and often have significant adverse side effects. Loring’s group at TSRI has been searching for another way to treat MS using human pluripotent stem cells, which are cells that have the potential to transform into any of the cell types in the body.
Loring’s group has been focused on turning human stem cells into neural precursor cells, which are an intermediate cell type that can eventually develop into neurons and other kinds of cells in the nervous system. In collaboration with Lane’s group, Loring’s team has been testing the effects of implanting human neural precursor cells into the spinal cords of mice that have been infected with a virus that induces symptoms of MS.
A Domino Effect
The transformation that took place in the largely immobilized mice after the human neural precursor cells were injected into the animals’ damaged spinal cords was dramatic. “Tom called me up and said, ‘You’re not going to believe this,’” Loring said. “He sent me a video, and it showed the mice running around the cages. I said, ‘Are you sure these are the same mice?’”
Even more remarkable, the animals continued walking even after the human cells were rejected, which occurred about a week after implantation. This suggests that the human stem cells were secreting a protein or proteins that had a long-lasting effect on preventing or impeding the progression of MS in the mice, said Ron Coleman, a TSRI graduate student in Loring’s lab who was first author of the paper with Lu Chen of UC Irvine. “Once the human stem cells kick that first domino, the cells can be removed and the process will go on because they’ve initiated a cascade of events,” said Coleman.
The scientists showed in the new study that the implanted human stem cells triggered the creation of white blood cells known as regulatory T cells, which are responsible for shutting down the autoimmune response at the end of an inflammation. In addition, the implanted cells released proteins that signaled cells to re-myelinate the nerve cells that had been stripped of their protective sheaths.
A Happy Accident
The particular line of human neural precursor cells used to heal the mice was the result of a lucky break. Coleman was using a common technique for coaxing human stem cells into neural precursor cells, but decided partway through the process to deviate from the standard protocol. In particular, he transferred the developing cells to another Petri dish.
“I wanted the cells to all have similar properties, and they looked really different when I didn’t transfer them,” said Coleman, who was motivated to study MS after his mother died from the disease. This step, called “passaging,” proved key. “It turns out that passaging alters the types of proteins that the cells express,” he said.
Loring called the creation of the successful neural precursor cell line a “happy accident.” “If we had used common techniques to create the cells, they wouldn’t have worked,” she said. “We’ve shown that now. There are a dozen different ways to make neural precursor cells, and only this one has worked so far. We now know that it is incredibly important to make the cells the same way every time.”
Hot On the Trail
The team is now working to discover the particular proteins that its unique line of human precursor cells release. One promising candidate is a class of proteins known as transforming growth factor beta, or TGF-B, which other studies have shown is involved the creation of regulatory T cells. Experiments by the scientists showed that the human neural precursor cells released TGF-B proteins while they were inside the spinal cords of the impaired mice. However, it’s also likely that other, as yet unidentified, protein factors may also be involved in the mice’s healing.
If the team can pinpoint which proteins released by the neural precursor cells are responsible for the animals’ recovery, it may be possible to devise MS treatments that don’t involve the use of human stem cells. “Once we identify the factors that are responsible for healing, we could make a drug out of them,” said Lane. Another possibility, Loring said, might be to infuse the spinal cords of humans affected by MS with the protein factors that promote healing.
A better understanding of what makes these human neural precursor cells effective in mice will be key to developing either of these therapies for humans. “We’re on the trail now of what these cells do and how they work,” Loring said.
(Source: scripps.edu)
How your brain works during meditation
Mindfulness. Zen. Acem. Meditation drumming. Chakra. Buddhist and transcendental meditation. There are countless ways of meditating, but the purpose behind them all remains basically the same: more peace, less stress, better concentration, greater self-awareness and better processing of thoughts and feelings.
But which of these techniques should a poor stressed-out wretch choose? What does the research say? Very little – at least until now.
Nondirective or concentrative meditation?
A team of researchers at the Norwegian University of Science and Technology (NTNU), the University of Oslo and the University of Sydney is now working to determine how the brain works during different kinds of meditation.
Different meditation techniques can actually be divided into two main groups. One type is concentrative meditation, where the meditating person focuses attention on his or her breathing or on specific thoughts, and in doing so, suppresses other thoughts. The other type may be called nondirective meditation, where the person who is meditating effortlessly focuses on his or her breathing or on a meditation sound, but beyond that the mind is allowed to wander as it pleases. Some modern meditation methods are of this nondirective kind.
“No one knows how the brain works when you meditate. That is why I’d like to study it,” says Jian Xu, who is a physician at St. Olavs Hospital and a researcher at the Department of Circulation and Medical Imaging at NTNU.
Two different ways to meditate
Fourteen people who had extensive experience with the Norwegian technique Acem meditation were tested in an MRI machine. In addition to simple resting, they undertook two different mental meditation activities, nondirective meditation and a more concentrative meditation task. The research team wanted to test people who were used to meditation because it meant fewer misunderstandings about what the subjects should actually be doing while they lay in the MRI machine.
The results were recently published in the journal “Frontiers in Human Neuroscience”.
Nondirective meditation led to higher activity than during rest in the part of the brain dedicated to processing self-related thoughts and feelings. When test subjects performed concentrative meditation, the activity in this part of the brain was almost the same as when they were just resting.
A place for the mind to rest
“I was surprised that the activity of the brain was greatest when the person’s thoughts wandered freely on their own, rather than when the brain worked to be more strongly focused,” said Xu. “When the subjects stopped doing a specific task and were not really doing anything special, there was an increase in activity in the area of the brain where we process thoughts and feelings. It is described as a kind of resting network. And it was this area that was most active during nondirective meditation.”
Provides greater freedom for the brain
“The study indicates that nondirective meditation allows for more room to process memories and emotions than during concentrated meditation,” says Svend Davanger, a neuroscientist at the University of Oslo, and co-author of the study.
“This area of the brain has its highest activity when we rest. It represents a kind of basic operating system, a resting network that takes over when external tasks do not require our attention. It is remarkable that a mental task like nondirective meditation results in even higher activity in this network than regular rest,” says Davanger.
Meditating researchers
Most of the research team behind the study do not practice meditation, although three do: Professors Are Holen and Øyvind Ellingsen from NTNU and Professor Svend Davanger from the University of Oslo.
Acem meditation is a technique that falls under the category of nondirective meditation. Davanger believes that good research depends on having a team that can combine personal experience with meditation with a critical attitude towards results.
“Meditation is an activity that is practiced by millions of people. It is important that we find out how this really works. In recent years there has been a sharp increase in international research on meditation. Several prestigious universities in the US spend a great deal of money to research in the field. So I think it is important that we are also active,” says Davanger.
How Cone Snail Venom Minimizes Pain
The venom from marine cone snails, used to immobilize prey, contains numerous peptides called conotoxins, some of which can act as painkillers in mammals. A recent study in The Journal of General Physiology provides new insight into the mechanisms by which one conotoxin, Vc1.1, inhibits pain. The findings help explain the analgesic powers of this naturally occurring toxin and could eventually lead to the development of synthetic forms of Vc1.1 to treat certain types of neuropathic pain in humans.
Neuropathic pain, a form of chronic pain that occurs in conjunction with injury to—or dysfunction of—the nervous system, can be debilitating and difficult to treat, and the medical community is eager to find better methods to minimize what can be a serious condition. Neuropathic pain is associated with changes in the transmission of signals between neurons, a process that depends on several types of voltage-gated calcium channels (VGCCs). However, given the importance of these VGCCs in mediating normal neurotransmission, using them as a pharmacological target against neuropathic pain could potentially lead to undesirable side effects.
In previous studies, David Adams and colleagues from RMIT University in Melbourne showed that Vc1.1 acted against neuropathic pain in mice; they found that, rather than acting directly to block VGCCs, Vc1.1 acts through GABA type B (GABAB) receptors to inhibit N-type (Cav2.2) channels.
Now, Adams and colleagues show that Vc1.1 also acts through GABAB receptors to inhibit a second, mysterious class of neuronal VGCCs that have been implicated in pain signaling but have not been well understood—R-type (Cav2.3) channels. Their new findings not only help solve the mystery of Cav2.3 function, but identify them as targets for analgesic conotoxins.
Training the Brain to Focus
About one in 10 school children suffers from attention deficit/hyperactivity disorder (ADHD), according to the Centers for Disease Control and Prevention. Linked to measurable differences in children’s brain structures and brain waves, ADHD can have dire effects on children’s academic achievements and lead to disrupted classrooms.
The CDC reports that as many as 3 million American elementary school children now take medications to control their symptoms. But these drugs don’t work for everyone. Worse, their potential side effects can have serious consequences for kids who also have heart conditions, eating or digestive problems or mood disorders such as depression.
In a recent study, Naomi J. Steiner, director of the CATS Project (Computer Attention Training in Schools for children with ADHD) at Tufts Medical Center, and her colleagues found that computer-based attention-training exercises significantly improved the ability of kids with ADHD to focus and pay attention.
The team tested two kinds of computer training systems. The first, computer cognitive attention training, uses computerized brain exercises to strengthen key mental skills such as short-term memory, eye-hand coordination and visual processing through a series of game-like activities. The second, neurofeedback, measures children’s brain waves in real time and provides visual and auditory feedback that can help them harness their ability to focus. The researchers found that both systems ameliorated the symptoms of ADHD, with neurofeedback outperforming computer cognitive attention training.
What’s more, the team found that the effect lasted months after the computer-based training sessions ended. The results of the large-scale clinical trial, published earlier this year in the journal Pediatrics, bolster the positive findings Steiner and her colleagues saw in a pilot study they conducted previously.
That’s encouraging news, because these therapies—some of which are commercially available to the public and many of which have been adopted by school systems in every state—aren’t yet covered by health insurance policies, nor will they be without a data showing their efficacy. Steiner’s body of research is one more step down that road. (See the story “Your Brain on Video Games.”)
(Image: Shutterstock)
A National Institutes of Health-sponsored study published in the Journal of the American Medical Association (JAMA) showed that lorazepam - a widely used but not yet Food and Drug Administration (FDA) approved drug for children - is no more effective than an approved benzodiazepine, diazepam, for treating pediatric status epilepticus.
Status epilepticus is a state in which the brain is in a persistent state of seizure. By the age of 15, 4 to 8 percent of children experience a seizure episode, which can be life threatening if they aren’t stopped immediately. Status epilepticus is a continuous, unremitting seizure lasting longer than five minutes or recurrent seizures without regaining consciousness between seizures for more than five minutes.
Before this current study, published April 23, there was no evidence indicating which of the two treatments might prove more effective. Although it is not yet approved by the FDA, James M. Chamberlain, MD, Division Chief of Emergency Medicine at Children’s National Health System, the study’s principal investigator, estimates that lorazepam is used as first-line therapy in most emergency departments.
“The study results provide reassurance to emergency medicine personnel who must act within minutes,” said Chamberlain. The study was conducted at 11 hospitals in the United States using the infrastructure of the Pediatric Emergency Care Applied Research Network (PECARN), under a contract from the National Institutes of Health’s (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
Both lorazepam and diazepam are used to treat status epilepticus. Diazepam, also known as Valium, is the only one of the two drugs to have been approved by the FDA for use in adults and children.
Lorazepam, marketed under the trade name Ativan, has been approved by the FDA only for use in adults. Once the FDA has approved a drug for use in adults, physicians may then prescribe it for other uses and in pediatric patients if, in their best judgment, they believe their patients will benefit.
“Sometimes physicians are forced to rely on their best judgment alone,” said George Giacoia, MD, of the NICHD’s Obstetric and Pediatric Pharmacology and Therapeutics Branch. “However, it’s always better to make treatment decisions on the evidence that comes only from conducting large comparison studies. We now know that lorezapam offers no advantage over diazepam in treating pediatric seizure disorder, and that diazepam is more suited to use by emergency teams.”
In 2007, the National Institutes of Health’s Pediatric Seizure study sought to determine which of two drugs—diazepam or lorazepam—was more effective in treating the life-threatening condition, status epilepticus. This condition can occur without warning. For reasons not fully understood, a child may be gripped by continuous seizures, which, if not stopped within minutes, may lead to brain damage or even death.
Because of the random nature of seizures and their significantly life altering affects, lorezapam is commonly prescribed to treat status epilepticus in children, even though it hasn’t been specifically approved for that use. The results of the Pediatric Seizure study do not support the use of lorezapam instead of diazepam for treating status epilepticus, Dr. Chamberlain said. Also, because lorezapam needs to be refrigerated and diazepam does not, diazepam is more suited for use by ambulance crews.
A few previous studies indicated that lorazepam might be more effective at ending a seizure and might be less likely than diazepam to depress breathing—a side effect of benzodiazapines, the category of medications that includes both drugs.
In their study, Chamberlain and colleague wrote, “There is no conclusive evidence to support lorazepam as a superior treatment and there is little consensus as to which is the preferred agent.”
The current study was the largest, most comprehensive comparison study of the two treatments for pediatric seizure disorder. Dr. Chamberlain and his colleagues enrolled 310 children at the 11 institutions, between 2008 and 2012. The researchers found that both medications successfully halted seizures in 70 percent of cases, and each had rates of severe respiratory depression of less than 20 percent.
It’s important that “we get the most important scientific information about such medications so there are government approvals for pediatric use,” Chamberlain said. “Pediatric patients are not just small adults.”
(Image: Alamy)
Preventing Alzheimer’s disease — with an antidepressant
Citalopram, an antidepressant better known by its commercial name Celexa, has a remarkable side effect, a new study has found: In both mice bred to develop Alzheimer’s disease and in healthy human volunteers, the selective serotonin reuptake inhibitor, or SSRI, drives down the production of a protein called beta-amyloid, which in the brains of those with Alzheimer’s clumps together in sticky plaques and is thought to short-circuit the brain’s wiring.
In study participants free of Alzheimer’s disease or any other neuropsychiatric affliction, citalopram was found to reduce the concentration of beta-amyloid in the cerebrospinal fluid (outside of the brain) by 38%. Researchers see that as a clear sign that beta-amyloid protein in the brain, too, declines in those taking the antidepressant.
(Image caption: Omega-3 fatty acid DHA transporter protein Mfsd2a is shown here as red fluorescence along mouse brain capillaries. Credit: Long N. Nguyen)
Researchers discover how DHA omega-3 fatty acid reaches the brain
It is widely believed that DHA (docosahexaenoic acid) is good for your brain, but how it is absorbed by the brain has been unknown. That is - until now. Researchers from Duke-NUS Graduate Medical School Singapore (Duke-NUS) have conducted a new study identifying that the transporter protein Mfsd2a carries DHA to the brain. Their findings have widespread implications for how DHA functions in human nutrition.
People know that DHA is an essential dietary nutrient that they can get from seafood and marine oils. Baby formula companies are especially attuned to the benefits of DHA, with nary a baby formula marketed without it.
DHA is an omega-3 fatty acid most abundantly found in the brain that is thought to be crucial to its function. However, the brain does not produce DHA. Instead, DHA uptake in the brain happens in two ways. The developing brain receives DHA during fetal development, from a mother to her baby. The adult brain gets it through food or DHA produced by the liver.
Though DHA is postulated to benefit the brain, the mechanics of how the brain absorbs the fatty acid has remained elusive. Senior author of the research, Associate Professor David L. Silver of Duke-NUS explained the importance of unlocking this mystery.
"If we could show the link by determining how DHA gets into the brain, then we could use this information to more effectively target its absorption and formulate an improved nutritional agent."
In the study, led by post-doctoral fellow Long N. Nguyen of Duke-NUS, researchers found that mice without the Mfsd2a transporter had brains a third smaller than those with the transporter, and exhibited memory and learning deficits and high levels of anxiety. The team recognized that the learning, memory and behavioral function of these mice were reminiscent of omega-3 fatty acid deficiency in mice starved of DHA in their diet.
Then, using biochemical approaches, the team discovered that mice without Mfsd2a were deficient in DHA and made the surprising discovery that Mfds2a transports DHA in the chemical form of lysophosphatidlycholine (LPC). LPCs are phospholipids mainly produced by the liver that circulate in human blood at high levels. This is an especially significant finding as LPCs have been considered toxic to cells and their role in the body remains poorly understood. Based on this surprising new information, Dr Silver’s team showed that Mfsd2a is the major pathway for the uptake of DHA carried in the chemical form of LPCs by the growing fetal brain and by adult brain.
The findings, published online in Nature the week of May 12, 2014 marks the first time a genetic model for brain DHA deficiency and its functions in the brain has been made available.
"Our findings can help guide the development of technologies to more effectively incorporate DHA into food and exploit this pathway to maximize the potential for improved nutritionals to improve brain growth and function. This is especially important for pre-term babies who would not have received sufficient DHA during fetal development," said Dr Silver, who is from the Cardiovascular and Metabolic Disorders Program at Duke-NUS.
(Image caption: Tracer dye (red) leaked through capillaries (green) in the brains of mice that lacked the gene Mfsd2a, helping to reveal the gene’s role in regulating blood-brain barrier permeability. Credit: Gu Lab)
Like a bouncer at an exclusive nightclub, the blood-brain barrier allows only select molecules to pass from the bloodstream into the fluid that bathes the brain. Vital nutrients get in; toxins and pathogens are blocked. The barrier also ensures that waste products are filtered out of the brain and whisked away.
The blood-brain barrier helps maintain the delicate environment that allows the human brain to thrive. There’s just one problem: The barrier is so discerning, it won’t let medicines pass through. Researchers haven’t been able to coax it to open up because they don’t know enough about how the barrier forms or functions.
Now, a team from Harvard Medical School has identified a gene in mice, Mfsd2a, that may be responsible for limiting the barrier’s permeability—and the molecule it produces, Mfsd2a, works in a way few researchers expected.
“Right now, 98 percent of small-molecule drugs and 100 percent of large-molecule drugs and antibodies can’t get through the blood-brain barrier,” said Chenghua Gu, associate professor of neurobiology at HMS and senior author of the study. “Less than 1 percent of pharmaceuticals even try to target the barrier, because we don’t know what the targets are. Mfsd2a could be one.”
Most attempts to understand and manipulate blood-brain barrier function have focused on tight junctions, seals that prevent all but a few substances from squeezing between barrier cells. Gu and her team discovered that Mfsd2a appears to instead affect a second barrier-crossing mechanism that has received much less attention, transcytosis, a process in which substances are transported through the barrier cells in bubbles called vesicles. Transcytosis occurs frequently at other sites in the body but is normally suppressed at the blood-brain barrier. Mfsd2a may be one of the suppressors.
“It’s exciting because this is the first molecule identified that inhibits transcytosis,” said Gu. “It opens up a new way of thinking about how to design strategies to deliver drugs to the central nervous system.”
Because Mfsd2a has a human equivalent, blocking its activity in people could allow doctors to open the blood-brain barrier briefly and selectively to let in drugs to treat life-threatening conditions such as brain tumors and infections.
Conversely, because researchers have begun to link blood-brain barrier degradation to several brain diseases, boosting Mfsd2a or Mfsd2a could allow doctors to strengthen the barrier and perhaps alleviate diseases such as Alzheimer’s, amyotrophic lateral sclerosis (ALS) and multiple sclerosis. The findings may also have implications for other areas of the body that rely on transcytosis, such as the retina and kidney.
The study was published May 14 in Nature.
Back to the beginning
As developmental biologists, Gu and her colleagues believed watching the barrier develop in young organisms would reveal molecules important for its formation and function.
The team introduced a small amount of dye into the blood of embryonic mice at different stages of development and watched whether it leaked through the walls of the tiny capillaries of the mice’s brains, suggesting that the blood-brain barrier hadn’t formed yet, or stayed contained within the capillaries, indicating that the barrier was doing its job. This allowed them to define a time window during which the barrier was being built.
The team was able to do this by devising a new dye injection technique. Researchers studying blood-brain barrier leakage in adult organisms can inject dye directly into blood vessels, but the capillaries of embryos are too small and delicate. Instead, researchers typically inject dye into the heart. However, according to Gu, this can raise blood pressure and burst brain capillaries, making it difficult to tell whether leakage is due to blood-brain barrier immaturity or the dye procedure itself. She and her team used their vascular biology expertise to identify an alternate injection site that would avoid such artifacts: the liver.
“This allowed us to provide definitive evidence that the blood-brain barrier comes into play during embryonic development,” said Ayal Ben-Zvi, a postdoctoral researcher in the Gu lab and first author of the study. “That changes our understanding of the development of the brain itself.”
Telltale pattern
Now that they knew when the barrier formed in the mice, the team compared endothelial cells—the cells that line blood vessel walls and help form the blood-brain barrier—from peripheral blood vessels and cortical (brain) vessels and looked for differences in gene expression. They made a list of genes that were expressed only in the cortical endothelial cells. From that list, they validated about a dozen in vivo.
The team could have studied any of the genes first, but they were most intrigued by Mfsd2a because of its expression pattern. In addition to being switched on in brain vessels, it was active in the placenta and testis, two other organs that have barrier-type functions. Also, the gene is shared across vertebrate organisms that have blood-brain barriers, including humans.
Gu and the team then conducted experiments in mice that lacked the Mfsd2a gene. They found that without Mfsd2a, the blood-brain barrier leaked (although it didn’t prevent the blood vessels themselves from forming in the first place). The next question was why.
“We focused on two basic characteristics: tight junctions between cells, which prohibit passage of water-soluble molecules, and transcytosis, which happens all the time in peripheral vessels but very little in the cortical vessels,” said Gu. “We found the surprising result that Mfsd2a regulates transcytosis without affecting tight junctions. This is exciting because conceptually it says this previously unappreciated feature may be even more important than tight junctions.”
“At first we were looking at tight junctions, because we were also biased by the field,” said Ben-Zvi, who will be starting his own lab later this year at The Hebrew University of Jerusalem. “We weren’t finding anything on the electron micrographs even though we knew the vessels leaked. Then we noticed there were tons of vesicles.
“It really shows that if you do systematic science and see something strange, you shouldn’t dismiss it, because maybe that’s what you’re looking for.”
Next steps
The team also began to study the relationship between the cortical endothelial cells and another contributor to the blood-brain barrier, cells called pericytes. So far, they have found that pericytes regulate Mfsd2a. Next, they want to learn what exactly the pericytes are telling the endothelial cells to do.
Other future work in the Gu lab includes testing the dozen other potential molecular players and trying to piece together the entire network that regulates transcytosis in the blood-brain barrier.
“In addition to Mfsd2a, there may be several other molecules on the list that will be good drug targets,” said Gu. “The key here is we are gaining tools to manipulate transcytosis either way: opening or tightening.”
As important as the molecules themselves, she added, is the concept.
“I personally hope people in the blood-brain barrier field will consider the mind-shifting paradigm that transcytosis could be targeted or modulated,” said Ben-Zvi.
Better understanding—and potentially being able to manipulate—the molecular underpinnings of transcytosis could aid in the study and treatment of diseases in tissues beyond the brain, from the intestines absorbing nutrients to the kidneys filtering waste.
Being able to open and close the blood-brain barrier also promises to benefit basic research, enabling scientists to investigate how abnormal barrier formation affects brain development and what the relationship may be between barrier deterioration and disease.