1. Study suggests mutations in neurons accumulate with age; may explain normal cognitive decline and neurodegeneration

    January 2, 2018 by Ashley

    From the Boston Children’s Hospital press release:

    Scientists have wondered whether somatic (non-inherited) mutations play a role in aging and brain degeneration, but until recently there was no good technology to test this idea. A study published online today in Science, led by researchers from Boston Children’s Hospital and Harvard Medical School, used whole-genome sequencing of individual neurons and found strong evidence that brain mutations accumulate as we age. They also found that mutations accumulate at a higher rate in people with genetic premature aging disorders causing early brain degeneration.

    “It’s been an age-old question as to whether DNA mutations can accumulate in neurons — which usually don’t divide — and whether they are responsible for the loss of function that the brain undergoes as we get older,” says Christopher A. Walsh, MD, PhD, chief of the Division of Genetics and Genomics at Boston Children’s and co-senior author on the paper. “It hasn’t been possible to answer this question before, because we couldn’t sequence the genome of a single cell, and each mutation accumulated is unique to each cell.”

    Testing neurons one by one

    The research team tested DNA from 161 single neurons, taken from postmortem samples from the NIH NeuroBioBank. They came from 15 neurologically normal people of different ages (4 months to 82 years) and nine people with one of two accelerated aging and early-onset neurodegenerative disorders: Cockayne syndrome and xeroderma pigmentosum.

    Using the latest experimental and data analysis techniques, the team was able to detect mutations as small as single-letter changes in each neuron’s genetic code. Each cell had to have its genome amplified — by generating a multitude of copies — before its DNA sequence could be determined, and a large amount of data had to be analyzed.

    “Because many experimental artifacts arise during the single-cell experiments, a new computational method that can distinguish true mutations from the experimental noise was critical to the success of the project,” says Peter J. Park, PhD, of Harvard Medical School’s Department of Biomedical Informatics (DBMI), the paper’s other co-senior author.

    The neurons tested came from two areas of the brain implicated in age-related cognitive decline: the prefrontal cortex (the part of the brain most highly developed in humans) and the dentate gyrus of the hippocampus (a focal point in age-related degenerative conditions like Alzheimer’s).

    In neurons from neurologically normal people, the number of genetic mutations increased with age in both brain areas. However, mutations accumulated at a higher rate in the dentate gyrus. The researchers think this may be because the neurons have the ability to divide, unlike their counterparts in the prefrontal cortex.

    In neurons from people with Cockayne syndrome and xeroderma pigmentosum, there was an increase in mutations in the prefrontal cortex over time — more than two-fold compared to the normal rate. Additionally, the researchers found that the portions of the genome that neurons used the most accumulated mutations at the highest rate, with help from collaborators at WuXi NextCODE.

    The aging genome

    The researchers coined the term “genosenium” — combining the concepts of genome and senescence/senility — to capture the idea of gradual and inevitable accumulation of mutations contributing to brain aging.

    The mutations themselves fell into three categories. “We were able to take all the mutations we found and use mathematical techniques to deconstruct them into different types of DNA changes,” says Michael Lodato, PhD, one of six co-first authors on the paper. “It’s like hearing an orchestra and teasing out the different instruments.”


  2. Researchers use WWII code-breaking techniques to interpret brain data

    January 1, 2018 by Ashley

    From the University of Pennsylvania press release:

    Cracking the German Enigma code is considered to be one of the decisive factors that hastened Allied victory in World War II. Starting with clues derived from espionage, computer scientists were able to work out the rules that turned a string of gibberish characters into plain German, providing life-saving and war-shortening intelligence.

    A team of researchers from the University of Pennsylvania, the Georgia Institute of Technology, and Northwestern University have now accomplished a similar feat, using cryptographic techniques to decode the activity of motor neurons. Their approach has allowed them to predict, from brain data, and with only generic knowledge of typical movements, which direction monkeys will move their arms.

    The same cryptography-inspired technique could eventually be used to decode more complex patterns of muscle activation, for use in prosthetic devices, or even speech, to aid those with total paralysis.

    The research team was led by Konrad Kording, a Penn Integrates Knowledge Professor with appointments in the Department of Neuroscience in Penn’s Perelman School of Medicine and in the Department of Bioengineering in the School of Engineering and Applied Science, and Eva Dyer, then a postdoctoral researcher in Kording’s lab and now an assistant professor in the Department of Biomedical Engineering at the Georgia Institute of Technology and Emory University. They collaborated with the group of Lee Miller, a professor of physiology at Northwestern University.

    The researchers published their study in the journal Nature Biomedical Engineering.

    In an experiment with three rhesus macaques, the researchers took data from several hundred neurons associated with arm movement. As the monkeys completed tasks where they had to reach to a target that appeared at different points around a central starting point, in-dwelling electrodes recorded spikes of electrical activity that corresponded with the movement of the monkey’s arm.


  3. Charting how brain signals connect to neurons

    December 31, 2017 by Ashley

    From the Johns Hopkins Medicine press release:

    Scientists at Johns Hopkins have used supercomputers to create an atomic scale map that tracks how the signaling chemical glutamate binds to a neuron in the brain. The findings, say the scientists, shed light on the dynamic physics of the chemical’s pathway, as well as the speed of nerve cell communications.

    It’s long been known that brain neurons use glutamate as a way to communicate with each other. As one neuron releases glutamate, an adjacent neuron latches onto the chemical through a structure on the neuron’s surface called a receptor. The glutamate-receptor connection triggers a neuron to open chemical channels that let in charged particles called ions, creating an electric spark that activates the neuron.

    “All of this happens within a millisecond, and what hasn’t been known is the way receptors latch onto glutamate. Our new experiments suggest that glutamate molecules need to take very particular pathways on the surface of glutamate receptors in order to fit into a pocket within the receptor,” says Albert Lau, Ph.D., assistant professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine.

    For the research, the Johns Hopkins scientists used a supercomputer called Anton, which is run by the Pittsburgh Supercomputing Center. They also worked with researchers at Humboldt University in Berlin who specialize in recording how charged particles flow between biological membranes.

    A report of the experiments will be published in the Jan. 3 issue of Neuron.

    To develop their model of how glutamate might connect to brain cell receptors, Lau and Johns Hopkins research fellow Alvin Yu used a computing technique called molecular dynamic simulations, which was developed by Martin Karplus, Michael Levitt and Arieh Warshel and earned them a Nobel Prize in 2013. The simulations use Sir Isaac Newton’s laws of motion and a set of mathematical rules, or algorithms to assign energy functions to atoms and the substances made from those atoms.

    “It takes an enormous amount of computer processing power to do these types of simulations,” says Lau.

    In their experiment, Yu and Lau immersed glutamate molecules and a truncated version of the glutamate receptor in a water and sodium chloride solution. The supercomputer recorded dynamics and interactions among nearly 50,000 atoms in the solution.

    “There are many ways glutamate can connect with a receptor,” says Lau. But some pathways are more direct than others. “The difference is like taking the faster highway route versus local roads to get to a destination.”

    Yu and Lau counted how frequently they saw glutamate in every position on the receptor. It turns out that glutamate spends most of its time gliding into three distinct pathways.

    Zooming in more closely at those pathways, the scientists found that the chemical’s negatively charged atoms are guided by positively charged atoms on the neuron’s glutamate receptors.

    “What we see is an electrostatic connection, and the path glutamate follows is determined by where the charges are,” says Lau. In the world of physics, when two objects near each other have opposing electrical charges, they attract each other.

    Lau says that the positively charged residues on the glutamate receptor may have evolved to shorten the time that glutamate takes to find its binding pocket.

    To test this idea, Lau teamed up with scientists at Humboldt University to introduce mutations into the gene that codes for the glutamate receptor to change positively charged residues into either negatively charged or uncharged ones.

    Then, they measured the resulting electrical currents to determine if there was a change in the rate of the receptor’s activation in the presence of glutamate.

    The results of that experiment showed that mutated glutamate receptors activated at half the speed of the normal version of the receptor.

    “If, as we think is the case, communication between neurons has to happen at a particular rate for effective brain activity, then slowing down that rate means that the brain won’t work as well,” says Lau. “We believe that these glutamate receptors have evolved a way to speed up the binding process.”

    The scientists add that, in some cases, glutamate seems to be able to bind to the receptor upside down. When this happens, the glutamate receptor’s pocket can’t close entirely, possibly making it unable to fully open its channels to allow ions into the neuron.

    Lau says that further research is needed to determine if other compounds that target the glutamate receptor, such as quisqualic acid, which is found in the seeds of some flowering plants, tread the same three pathways that glutamate tends to follow.

    So far, Lau’s team has focused its computer simulations only on the main binding region of the glutamate receptor. The researchers plan to study other areas of glutamate receptors exposed to glutamate.

    The Johns Hopkins’ team collaborators in Berlin were Héctor Salazar and Andrew Plested.

    The research was funded by the National Institutes of Health’s National Institute of General Medical Sciences (R01GM094495), the European Commission GluActive grant and the German Research Foundation Cluster of Excellence NeuroCure grant.


  4. Study looks at why we can’t always stop what we’ve started

    December 19, 2017 by Ashley

    From the Johns Hopkins University press release:

    When we try to stop a body movement at the last second, perhaps to keep ourselves from stepping on what we just realized was ice, we can’t always do it — and Johns Hopkins University neuroscientists have figured out why.

    Stopping a planned behavior requires extremely fast choreography between several distinct areas of the brain, the researchers found. If we change our mind about taking that step even a few milliseconds after the original “go” message has been sent to our muscles, we simply can’t stop our feet.

    “We have to process all of these pieces of information quickly,” said senior author Susan Courtney, a professor of psychological and brain sciences. “The question is: When we do succeed, how do we do that? What needs to happen in order for us to stop in time?”

    These findings, which will appear Dec. 20 in the journal Neuron, map the neural basis for inhibiting movement. They help explain what’s going wrong in the brain when people fall more as they age and when addicts can’t stop binge behavior.

    Scientists had believed only one brain region was active when people changed plans. But the findings of Courtney’s team suggest it takes a lightning-fast interaction between two areas in the prefrontal cortex and another in the pre-motor cortex to stop, reverse or otherwise change a plan already in progress.

    There is even another brain area, Courtney says, that continues to process what we should have done if we are unable to stop. She jokingly calls it the “oops” area.

    In addition to all three areas of the brain communicating successfully, the key to being able to stop, the researchers found, is timing.

    Suppose you’re driving and approaching an intersection when the light turns yellow. You decide to accelerate and speed though. But just after you send that decision to the part of the brain that will move your foot to hit the gas, you notice a police car and change your mind.

    “Which plan is going to win?” said first author Kitty Z. Xu, a former Johns Hopkins graduate student who is now a researcher at Pinterest. “The sooner you see the police car after deciding to go through the light, the better your chance of being able to move your foot to the break instead.”

    And by soon, Xu means milliseconds.

    If you attempt to change your mind after 100 milliseconds or less, you most likely can. If it takes you 200 milliseconds or more — that’s less than a quarter of a second — you’re still going through with the original plan. That’s because the original signal is already on its way to the muscles by then — past the point of no return.

    “If you’re already executing the plan when you see the police car,” Xu said, “you’re going to go through the light.”

    The team devised a near-identical computer task for human and non-human subjects. While having their brain activity monitored, both the people and one monkey saw one of two shapes on the screen — one shape meant that blue means stop and yellow means go, the other shape meant the opposite. A black circle would then appear and participants would try to move their eyes to look at it quickly. But then a blue or yellow dot might appear, after varying lengths of time, and subjects would have to stop or continue their planned eye movement.

    The researchers were able to observe what happened across the full brain with the human fMRI results, while electrodes implanted in the monkey’s brain measured single cells. Having strong, converging results at both the macro and micro levels provided a more holistic view of how the prefrontal cortex and the pre-motor cortex communicate with each other to stop, Xu said.

    When these brain areas don’t properly communicate, or don’t interact fast enough, that’s when we run into trouble, Courtney says.

    “We know people with damage to these parts of the brain have trouble changing plans or inhibiting actions,” she said. “We know as we age, our brain slows down and it takes us longer to find words or to try to make these split-second plan changes. It could be part of the reason why old people fall.”

    Knowing more about how the brain can stop an intended activity could also be revealing for those dealing with addictions, Courtney said.

    “We think there are similar processes in ‘should I do this’ and ‘can I turn off that thought about the drink,'” Courtney said. “The sooner I can turn off the plan to drink, the less likely I’ll carry out the plan. It’s very relevant.”

    Co-authors included Brian Anderson, a former Johns Hopkins graduate student and postdoctoral researcher who is now an assistant professor at Texas A&M University; Erik Emeric, a research technologist at Johns Hopkins’ Zanvyl Krieger Mind/Brain Institute; Anthony W. Sali, a former Johns Hopkins graduate student who is now a postdoctoral researcher at Duke University; Veit Stuphorn, an associate professor of psychological and brain sciences at Johns Hopkins; and Steven Yantis, a professor of psychological and brain sciences at Johns Hopkins who died in 2014.

    This project was supported by the National Institute in Drug Abuse R01-DA013165 and RO1DA040990, and the National Institute of Neurological Disorders and Stroke, R01NS086104.


  5. Electrical stimulation in brain bypasses senses, instructs movement

    by Ashley

    From the University of Rochester Medical Center press release:

    The brain’s complex network of neurons enables us to interpret and effortlessly navigate and interact with the world around us. But when these links are damaged due to injury or stroke, critical tasks like perception and movement can be disrupted. New research is helping scientists figure out how to harness the brain’s plasticity to rewire these lost connections, an advance that could accelerate the development of neuro-prosthetics.

    A new study authored by Marc Schieber, M.D., Ph.D., and Kevin Mazurek, Ph.D. with the University of Rochester Medical Center Department of Neurology and the Del Monte Institute for Neuroscience, which appears in the journal Neuron, shows that very low levels of electrical stimulation delivered directly to an area of the brain responsible for motor function can instruct an appropriate response or action, essentially replacing the signals we would normally receive from the parts of the brain that process what we hear, see, and feel.

    “The analogy is what happens when we approach a red light,” said Schieber. “The light itself does not cause us to step on the brake, rather our brain has been trained to process this visual cue and send signals to another parts of the brain that control movement. In this study, what we describe is akin to replacing the red light with an electrical stimulation which the brain has learned to associate with the need to take an action that stops the car.”

    The findings could have significant implications for the development of brain-computer interfaces and neuro-prosthetics, which would allow a person to control a prosthetic device by tapping into the electrical activity of their brain.

    To be effective, these technologies must not only receive output from the brain but also deliver input. For example, can a mechanical arm tell the user that the object they are holding is hot or cold? However, delivering this information to the part of the brain responsible for processing sensory inputs does not work if this part of the brain is injured or the connections between it and the motor cortex are lost. In these instances, some form of input needs to be generated that replaces the signals that combine sensory perception with motor control and the brain needs to “learn” what these new signals mean.

    “Researchers have been interested primarily in stimulating the primary sensory cortices to input information into the brain,” said Schieber. “What we have shown in this study is that you don’t have to be in a sensory-receiving area in order for the subject to have an experience they can identify.”

    A similar approach is employed with cochlear implants for hearing loss which translate sounds into electrical stimulation of the inner ear and, over time, the brain learns to interpret these inputs as sound.

    In the new study, the researchers detail a set of experiments in which monkeys were trained to perform a task when presented with a visual cue, either turning, pushing, or pulling specific objects when prompted by different lights. While this occurred, the animals simultaneously received a very mild electrical stimulus called a micro-stimulation in different areas of the premotor cortex — the part of the brain that initiates movement — depending upon the task and light combination.

    The researchers then replicated the experiments, but this time omitted the visual cue of the lights and instead only delivered the micro-stimulation. The animals were able to successfully identify and perform the tasks they had learned to associate with the different electrical inputs. When the pairing of micro-stimulation with a particular action was reshuffled, the animals were able to adjust, indicating that the association between stimulation and a specific movement was learned and not fixed.

    “Most work on the development of inputs to the brain for use with brain-computer interfaces has focused primarily on the sensory areas of the brain,” said Mazurek. “In this study, we show you can expand the neural real estate that can be targeted for therapies. This could be very important for people who have lost function in areas of their brain due to stroke, injury, or other diseases. We can potentially bypass the damaged part of the brain where connections have been lost and deliver information to an intact part of the brain.”


  6. Study suggests neuron-pruning drug may nudge mice away from habit-driven behaviors when combined with retraining

    December 10, 2017 by Ashley

    From the Emory Health Sciences press release:

    A drug that stimulates neuron pruning can nudge mice away from habit-driven behaviors when combined with retraining, neuroscientists have found.

    The results were published online on November 30 by Nature Communications.

    The drug fasudil, approved in Japan for cerebral vasospasm and stroke, inhibits an enzyme that stabilizes cells’ internal skeletons. The researchers suggest that fasudil or similar compounds could be effective tools for facilitating the treatment of drug abuse and preventing relapse.

    A large fraction of the actions people perform each day come from habits, not from deliberate decision making. Going on auto-pilot can free up attention for new things, but it can also be detrimental, in the case of drug abuse and drug-seeking behavior, says lead author Shannon Gourley, PhD, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.

    “Some habits are adaptive — for example, turning off a light when you exit a room — but others can be maladaptive, for example in the case of habitual drug use. We wanted to try to figure out a way to help ‘break’ habits, particularly those related to the highly-addictive drug cocaine,” says Gourley.

    Gourley and former graduate students Andrew Swanson, PhD and Lauren Depoy, PhD tested fasudil in situations where they had trained mice to poke their noses in two chambers, based on rewards of both food and cocaine. Then the researchers changed the rules of the game. The mice had to learn something new, in terms of where to poke their noses to get the reward.

    In particular, the mice could now only get a reward from one chamber instead of both. Fasudil helped the mice adjust and display “goal-directed” behavior, rather than their previous habit-based behavior.

    In addition, the researchers trained the mice to supply themselves a sweet cocaine solution. Then they changed the nature of that experience: the cocaine was paired with lithium chloride, which made the mice feel sick. Fasudil treatment nudged the mice to give themselves less cocaine afterwards, rather than continuing to respond habitually. The scientists envision this as modeling negative experiences associated with cocaine use in humans.

    “Humans may seek treatment due to the negative consequences of cocaine abuse, but many people still relapse. We’re trying to strengthen the goal of abstaining from drug taking,” says Gourley.

    The researchers conducted additional experiments that revealed that fasudil didn’t make cocaine itself less pleasurable, but was specifically modifying the habit process. Also, fasudil did not affect other forms of decision making.

    Un-learning of habits involves remodeling connections made by cells in the brain. In the mouse retraining experiments, the way that fasudil seems to work is that it promotes the pruning of dendritic spines. Dendritic spines are structures that help neurons communicate and embody the strength of connections between them.

    Fasudil inhibits Rho kinase, which stabilizes F-actin, a major component of cells’ internal skeletons. Thus, it loosens up cell structures. And in mice, fasudil appears to slightly reduce the density of dendritic spines in a region of the brain that is important for learning new behaviors.

    “In this context, we imagine that fasudil is optimizing signal-to-noise, so to speak, allowing this brain region to efficiently guide decision making,” says Gourley.

    When fasudil is given to the mice a day after training, no changes in spine density are seen, indicating that it must be paired with new learning to have that effect.

    Some caution is order, because overactive synaptic pruning is proposed to play roles in Alzheimer’s disease and schizophrenia. In their paper, the authors conclude:

    Pairing Rho kinase inhibitors with cognitive behavioral therapy in humans could be an effective pharmacological adjunct to reduce the rate of relapse… Given its favorable safety profile and our evidence that it can mitigate cocaine self-administration, fasudil is a strong candidate, with the caveats that we envision it administered as an adjunct to behavioral therapy and potentially during early phases of drug withdrawal.


  7. Neurobiology: The chemistry of memory

    December 4, 2017 by Ashley

    From the Ludwig-Maximilians-Universitaet Muenchen (LMU) press release:

    Learning requires the chemical adaptation of individual synapses. Researchers have now revealed the impact of an RNA-binding protein that is intimately involved in this process on learning and memory formation and learning processes.

    The formation of memories requires subtle changes in brain structures. This is because learning and memory are the result of the incessant modification of synapses — which provide the functional connections that enable nerve cells to communicate with one another. The long-term molecular alterations involved in this process are encoded by so-called messenger RNAs, which are produced in the nucleus of the neuron and must be transported to the appropriate synapses in order to program the synthesis of specific proteins “on-site.” In previous studies, LMU scientist Michael Kiebler has shown that the RNA-binding protein Staufen2 plays an essential role in conveying these mRNAs to their destinations. But exactly how this molecular process actually affects learning and behavior was not well understood. Now, a study carried out by the Kiebler group, in collaboration with Dusan Bartsch (Mannheim University) and Spanish colleagues (Seville University), has shed new light on this issue. The new work shows, for the first time, that reduced levels of Staufen2 are associated with a specific impairment of memory. The findings appear in the journal Genome Biology.

    The researchers made use of a genetic rat model that has been developed and refined over the past decade, in which the synthesis of Staufen2 can be conditionally and selectively suppressed in nerve cells in the forebrain. They then characterized the effects of reduced levels of Staufen2 protein on memory using behavioral tests that measure the efficacy of spatial, temporal and associative memory. These tasks are known to depend on synaptic plasticity, i.e. the ability to actively adjust the efficiency of communication between specific synaptic networks, in the hippocampus. The results clearly show that the reduction of Staufen2 in the forebrain has a negative impact on several aspects of memory. “Overall, long-term memory continues to function, and the rats remain capable of learning how to find a food source, for instance” — Kiebler says — “but when the mutants are asked to recall what they have learned after longer periods of time, their performance is significantly worse than wild-type animals.”

    Depletion of Staufen2 also has a marked effect on nerve-cell morphology and synapse function. With the aid of electrophysiological measurements, the authors analyzed the efficiency of signal transmission across synapses in the hippocampus, and found that both long-term potentiation (LTP) and long-term depression (LTD) are affected. LTP is a mechanism that results in a long-lasting increase in the efficiency of synaptic transmission, and thus strengthens the functional connections between them. LTD, on the other hand, diminishes transmission efficacies, and effectively disconnects previously established connections. Strikingly, reduced levels of Staufen2 enhance LTP, while they impair LTD. These findings suggest that deficiency of Staufen2 makes synapses more responsive than they would otherwise be. “LTP is regarded as a model of learning at the cellular level. However, our results indicate that it is actually the balance of LTP to LTD that is important. This is clearly perturbed in the absence of Staufen2,” Kiebler points out. The researchers therefore assume that, under these circumstances, synapses become highly responsive, and not enough are repressed. This could imply that information which is normally consolidated in long-term memory is prematurely destabilized or perhaps even wiped out. “This work has enabled us, for the first time, to link a specific molecular factor — the RNA-binding protein Staufen2 — with synaptic plasticity and learning,” Kiebler says. “Furthermore, our approach promises to yield completely new insights into the molecular mechanisms that mediate learning.”


  8. Study suggests Alzheimer’s Tau protein forms toxic complexes with cell membranes

    December 2, 2017 by Ashley

    From the École polytechnique fédérale de Lausanne press release:

    The brains of patients with Alzheimer’s disease contain characteristic tangles inside neurons. These tangles are formed when a protein called Tau aggregates into twisted fibrils. As a result, the neurons’ transport systems disintegrate, essential nutrients can’t move through, and the cells begin to die, affecting the brain’s functions and giving rise to the disease’s symptoms.

    Given its role in the pathology of Alzheimer’s disease, Tau protein has been extensively investigated. With several clinical trials of amyloid-targeting therapies failing recently, Tau has become one of the most actively pursued therapeutic targets for Alzheimer’s disease. However, questions still remain about how Tau spreads in the brain and kills neurons. The cell membrane has been shown to play a role in regulating Tau’s aggregation properties and physiological functions, but we still do not understand how the interplay between Tau and lipid membranes can lead to the loss of neurons seen in Alzheimer’s disease.

    Now, the lab of Hilal Lashuel at EPFL, in collaboration with the lab of Thomas Walz at the Rockefeller University, found that individual Tau proteins interact with and disrupt the cell membrane of neurons. This disruption gives rise to highly stable complexes made up of several Tau proteins as well as fat molecules (phospholipids) from the membrane.

    Subsequent studies showed that the protein/phospholipid complexes are more readily taken up by neurons compared to the fibril form of the protein, and induce toxicity in primary neurons of the hippocampus in vitro. The hippocampus is where memory is processed, and loss of hippocampal neurons is a classic symptom of Alzheimer’s disease. The complexes were detectable with an antibody (MC-1) that is used as a standard for detecting pathological conformations of Tau, meaning that they share some features of the pathological form of the protein.

    “Our goal was to identify the sequence and structural factors that drive Tau interaction with membranes and the formation of these complexes so that we can develop strategies to interfere with their formation and block their toxicity,” says Nadine Ait Bouziad, the PhD student who led the study.

    In collaboration with Professor David Eliezer at Weill Cornell School of Medical Sciences in New York, the researchers used Nuclear Magnetic Resonance (NMR) to gain insight into the structure of Tau in the core of the complexes. This revealed that the cores are made up of two small peptides, each only six amino acids long. These peptides are called PHF6* and PHF6, and they play important roles in driving Tau aggregation and assembly into fibrils. Their presence connects the protein/phospholipid complexes with the development of Alzheimer’s disease.

    Building on their findings, the researchers were able to produce mutant Tau protein. The introduced mutations disrupted Tau’s ability to interact with cell membranes, but did so without interfering with its ability to form fibrils. The idea behind this is that such mutants can be used to uncouple these two processes, which would allow researchers to investigate the effect that these membrane interactions have on the function, aggregation and toxicity of Tau in primary neuron cultures. This would be a first step in gaining a clearer picture of how Tau tangles begin to form, which would be critical if we are to develop efficient therapies to counteract their toxicity.

    “Our findings point toward a novel form of Tau protein/phospholipid complexes that might be part of a membrane-dependent mechanism that regulates Tau structure, oligomerization, toxicity, and possibly its normal and aberrant trafficking between and within neurons,” says Hilal Lashuel. “By developing tools that allow us to detect, disrupt and/or target these complexes, we hope to identify novel strategies to inhibit Tau aggregation, toxicity, and pathology spreading in the Alzheimer’s brain.”


  9. Dementia study sheds light on how damage spreads through brain

    December 1, 2017 by Ashley

    From the University of Edinburgh press release:

    Insights into how a key chemical disrupts brain cells in a common type of dementia have been revealed by scientists.

    Brain tissue from people with Dementia with Lewy Bodies (DLB) showed that the protein builds up in vital parts of neurons that connect cells and may jump from one cell to another through these connections.

    Scientists say the findings shed light on the causes of DLB and will help to accelerate the search for a treatment.

    The study, co-led by the University of Edinburgh, focused on synapses – shared connection points between brain cells that allow chemical and electrical signals to flow between cells. These signals are vital for forming memories and are key to brain health, experts say.

    Researchers showed that synapses in five people who had died with DLB contained clumps of the damaging protein, known as alpha-synuclein, which could contribute to dementia symptoms.

    Toxic alpha-synuclein was spotted in both sides of the synapses, suggesting that it may jump between cells through these connections. This sheds light on how damage could be spread through the brain.

    Similar findings were not seen in brain tissue from people who had died with Alzheimer’s disease or those without dementia.

    The discovery was made with extremely powerful technology, used in DLB for the first time, which allowed the scientists to view detailed images of over one million single synapses. Individual synapses are around 5000 times smaller than the thickness of a sheet of paper.

    Although alpha-synuclein clumps had been previously identified in DLB, their effects on synapses were unknown because of difficulties in studying them due to their tiny size.

    DLB is the third most common form of dementia after Alzheimer’s and vascular dementias, affecting around 100,000 people in the UK. It can cause severe memory loss as well as movement problems and there is no cure.

    Professor Tara Spires-Jones, Programme Lead at the UK Dementia Research Institute at the University of Edinburgh, who co-led the study, said: “DLB is a devastating condition and our findings suggest that it is at least partly driven by damage to synapses. These discoveries should invigorate the search for therapies aimed at reducing synaptic damage and open the possibility of targeting the spread of alpha-synuclein through the brain, which could stop disease progression in its tracks.”

    Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said: “This exciting research using cutting-edge technology sheds new light on the progression of DLB in the brain. The results provide convincing, measurable and visual evidence that toxic alpha-synuclein is disrupting synapses that could potentially contribute to the devastating symptoms of the disease.

    “We are extremely pleased our funding has helped produce these important results which demonstrate potential avenues for much-needed new treatments for people who are living with DLB. The research we fund would not be possible without the work of our tireless supporters who go to extraordinary lengths to allow talented researchers to make important new discoveries like these.”


  10. Study suggests potential treatment for autism, intellectual disability

    November 26, 2017 by Ashley

    From the University of Nebraska Medical Center (UNMC) press release:

    A breakthrough in finding the mechanism and a possible therapeutic fix for autism and intellectual disability has been made by a University of Nebraska Medical Center researcher and his team at the Munroe-Meyer Institute (MMI).

    Woo-Yang Kim, Ph.D., associate professor, developmental neuroscience, led a team of researchers from UNMC and Creighton University into a deeper exploration of a genetic mutation that reduces the function of certain neurons in the brain.

    Dr. Kim’s findings were published in this week’s online issue of Nature Neuroscience.

    “This is an exciting development because we have identified the pathological mechanism for a certain type of autism and intellectual disability,” Dr. Kim said.

    Recent studies have shown that the disorder occurs when a first-time mutation causes only one copy of the human AT-rich interactive domain 1B (ARID1B) gene to remain functional, but it was unknown how it led to abnormal cognitive and social behaviors.

    Autism spectrum disorder (ASD) impairs the ability of individuals to communicate and interact with others. About 75 percent of individuals with ASD also have intellectual disability, which is characterized by significant limitations in cognitive functions and adaptive behaviors.

    There are no drugs or genetic treatments to prevent ASD or intellectual disability; the only treatment options focus on behavioral management and educational and physical therapies.

    The team created and analyzed a genetically modified mouse and found that a mutated Arid1b gene impairs GABA neurons, the ‘downer’ neurotransmitter, leading to an imbalance of communication in the brain.

    GABA blocks impulses between nerve cells in the brain. Low levels of GABA may be linked to anxiety or mood disorders, epilepsy and chronic pain. It counters glutamate (the upper neurotransmitter), as the two mediate brain activation in a Yin and Yang manner. People take GABA supplements for anxiety.

    “In normal behavior, the brain is balanced between excitation and inhibition,” Dr. Kim said. “But when the inhibition is decreased, the balance is broken and the brain becomes more excited causing abnormal behavior.

    “We showed that cognitive and social deficits induced by an Arid1bmutation in mice are reversed by pharmacological treatment with a GABA receptor modulating drug. And, now we have a designer mouse that can be used for future studies.”

    Next steps for Dr. Kim and his team are to even further refine the specific mechanism for autism and intellectual disability and to identify which of the many GABA neurons are specifically involved.