Posts tagged neurodegenerative diseases
Articles and news from the latest research reports.
Scientists Help Unravel a Central Mystery of Alzheimer’s Disease
Scientists at The Scripps Research Institute (TSRI) have shed light on one of the major toxic mechanisms of Alzheimer’s disease. The discoveries could lead to a much better understanding of the Alzheimer’s process and how to prevent it.
The findings, reported in the April 10, 2013 issue of the journal Neuron, show that brain damage in Alzheimer’s disease is linked to the overactivation of an enzyme called AMPK. When the scientists blocked this enzyme in mouse models of the disease, neurons were protected from loss of synapses—neuron-to-neuron connection points—typical of the early phase of Alzheimer’s disease.
“These findings open up many new avenues of investigation, including the possibility of developing therapies that target the upstream mechanisms leading to AMPK overactivation in the brain,” said TSRI Professor Franck Polleux, who led the new study.
Alzheimer’s disease, a fatal neurodegenerative disorder afflicting more than 25 million people worldwide, currently has no cure or even disease-delaying therapy.
In addition to having implications for Alzheimer’s drug discovery, Polleux noted the findings suggest the need for further safety studies on an existing drug, metformin. Metformin, apopular treatment for Type 2 Diabetes, causes AMPK activation.
Tantalizing Clues to Alzheimer’s
Researchers have known for years that people in the earliest stages of Alzheimer’s disease begin to lose synapses in certain memory-related brain areas. Small aggregates of the protein amyloid beta can cause this loss of synapses, but how they do so has been a mystery.
Until recently, Polleux’s laboratory has been focused not on Alzheimer’s research but on the normal development and growth of neurons. In 2011, he and his colleagues reported that AMPK overactivation by metformin, among other compounds, in animal models impaired the ability of neurons to grow output stalks, or axons.
Around the same time, separate research groups found clues that AMPK might also have a role in Alzheimer’s disease. One group reported that AMPK can be activated in neurons by amyloid beta, which in turn can cause a modification of the protein tau in a process known as phosphorylation. Tangles of tau with multiple phosphorylations (“hyperphosphorylated” tau) are known to accumulate in neurons in affected brain areas in Alzheimer’s. These results, published two years ago, reported abnormally high levels of activated AMPK in these tangle-ridden neurons.
Polleux decided to investigate further, to determine whether the reported interactions of AMPK with amyloid beta and tau can in fact cause the damage seen in the brains of Alzheimer’s patients. “Very little was known about the function of this AMPK pathway in neurons, and we happened to have all the tools needed to study it,” he said.
In Search of Answers
Georges Mairet-Coello, a postdoctoral research associate in the Polleux lab, performed most of the experiments for the new study. He began by confirming that amyloid beta, in the small-aggregate (“oligomer”) form that is toxic to synapses, does indeed strongly activate AMPK; amyloid beta oligomers stimulate certain neuronal receptors, which in turn causes an influx of calcium ions into the neurons. He found that this calcium influx triggers the activation of an enzyme called CAMKK2, which appears to be the main activator of AMPK in neurons.
The team then showed that this AMPK overactivation in neurons is the essential reason for amyloid beta’s synapse-harming effect. Normally, the addition of amyloid beta oligomers to a culture of neurons causes the swift disappearance of many of the neurons’ dendritic spines—the rootlike, synapse-bearing input stalks that receive signals from other neurons. With a variety of tests, the scientists showed that amyloid beta oligomers can’t cause this dendritic spine loss unless AMPK overactivation occurs—and indeed AMPK overactivation on its own can cause the spine loss.
For a key experiment the team used J20 mice, which are genetically engineered to overproduce mutant amyloid beta, and eventually develop an Alzheimer’s-like condition. “When J20 mice are only three months old, they already show a strong decrease in dendritic spine density, in a set of memory-related neurons that are also affected early in human Alzheimer’s,” Mairet-Coello said. “But when we blocked the activity of CAMKK2 or AMPK in these neurons, we completely prevented the spine loss.”
Next Mairet-Coello investigated the role of the tau protein. Ordinarily it serves as a structural element in neuronal axons, but in Alzheimer’s it somehow becomes hyperphosphorylated and drifts into other neuronal areas, including dendrites where its presence is associated with spine loss. Recent studies have shown that amyloid beta’s toxicity to dendritic spines depends largely on the presence of tau, but just how the two Alzheimer’s proteins interact has been unclear.
The team took a cue from a 2004 study of Drosophila fruit flies, in which an AMPK-like enzyme’s phosphorylation of specific sites on the tau protein led to a cascade of further phosphorylations and the degeneration of nerve cells. The scientists confirmed that one of these sites, S262, is indeed phosphorylated by AMPK. They then showed that this specific phosphorylation of tau accounts to a significant extent for amyloid beta’s synapse toxicity. “Blocking the phosphorylation at S262, by using a mutant form of tau that can’t be phosphorylated at that site, prevented amyloid beta’s toxic effect on spine density,” Mairet-Coello said.
The result suggests that amyloid beta contributes to Alzheimer’s via AMPK, mostly as an enabler of tau’s toxicity.
More Studies Ahead
Mairet-Coello, Polleux and their colleagues are now following up with further experiments to determine what other toxic processes, such as excessive autophagy, are promoted by AMPK overactivation and might also contribute to the long-term aspects of Alzheimer’s disease progression. They are also interested in the long-term effects of blocking AMPK overactivation in the J20 mouse model as well as in other mouse models of Alzheimer’s disease, which normally develop cognitive deficits at later stages. “We already have contacts within the pharmaceuticals industry who are potentially interested in targeting either CAMKK2 or AMPK,” says Polleux.
The other contributors to the study, “The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of amyloid beta oligomers through tau phosphorylation,” were Julien Courchet, Simon Pieraut, Virginie Courchet and Anton Maximov, all of TSRI.
(Source: scripps.edu)
Lights, Chemistry, Action: New Method for Mapping Brain Activity
Building on their history of innovative brain-imaging techniques, scientists at the U.S. Department of Energy’s Brookhaven National Laboratory and collaborators have developed a new way to use light and chemistry to map brain activity in fully-awake, moving animals. The technique employs light-activated proteins to stimulate particular brain cells and positron emission tomography (PET) scans to trace the effects of that site-specific stimulation throughout the entire brain. As described in a paper published online today in the Journal of Neuroscience, the method will allow researchers to map exactly which downstream neurological pathways are activated or deactivated by stimulation of targeted brain regions, and how that brain activity correlates with particular behaviors and/or disease conditions.
"This technique gives us a new way to look at the function of specific brain cells and map which brain circuits are active in a wide range of neuropsychiatric diseases — from depression to Parkinson’s disease, neurodegenerative disorders, and drug addiction — and also to monitor the effects of various treatments," said the paper’s lead author, Panayotis (Peter) Thanos, a neuroscientist and director of the Behavioral Neuropharmacology and Neuroimaging Section — part of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) Laboratory of Neuroimaging at Brookhaven Lab — and a professor at Stony Brook University. "Because the animals are awake and able to move during stimulation, we can also directly study how their behavior correlates with brain activity," he said.
The new brain-mapping method combines very recent advances in a field known as “optogenetics” — the use of optics (light activation) and genetics (genetically coded light-sensitive proteins) to control the activity of individual neurons, or nerve cells — and Brookhaven’s historical development of radioactively labeled chemical tracers to track biological activity with PET scanners.
The scientists used a modified virus to deliver a light-sensitive protein to particular brain cells in rats. Genetic coding can deliver the protein to specifically targeted brain-cell receptors. Then, after stimulating those proteins with light shone through an optical fiber inserted through a tiny tube called a cannula, they monitored overall brain activity using a radiotracer known as 18FDG, which serves as a stand-in for glucose, the body’s (and brain’s) main source of energy.
The unique chemistry of 18FDG causes it to be temporarily “trapped” inside cells that are hungry for glucose — those activated by the brain stimulation — and remain there long enough for the detectors of a PET scanner to pick up the radioactive signal, even after the animals are anesthetized to ensure they stay still for scanning. But because the animals were awake and moving when the tracer was injected and the brain cells were being stimulated, the scans reveal what parts of the brain were activated (or deactivated) under those conditions, giving scientists important information about how those brain circuits function and correlate with the animals’ behaviors.
"In this paper, we wanted to stimulate the nucleus accumbens, a key part of the brain involved in reward that is very important to understanding drug addiction," Thanos said. "We wanted to activate the cells in that area and see which brain circuits were activated and deactivated in response."
The scientists used the technique to trace activation and deactivation in number of key pathways, and confirmed their results with other analysis techniques.
The method can reveal even more precise effects.
"If we want to know more about the role played by specific types of receptors — say the dopamine D1 or D2 receptors involved in processing reward — we could tailor the light-sensitive protein probe to specifically stimulate one or the other to tease out those effects," he said.
Another important aspect is that the technique does not require the scientists to identify in advance the regions of the brain they want to investigate, but instead provides candidate brain regions involved anywhere in the brain – even regions not well understood.
"We look at the whole brain," Thanos said. "We take the PET images and co-register them with anatomical maps produced with magnetic resonance imaging (MRI), and use statistical techniques to do comparisons voxel by voxel. That allows us to identify which areas are more or less activated under the conditions we are exploring without any prior bias about what regions should be showing effects.”
After they see a statistically significant effect, they use the MRI maps to identify the locations of those particular voxels to see what brain regions they are in.
"This opens it up to seeing an effect in any region in the brain — even parts where you would not expect or think to look — which could be a key to new discoveries," he said.
Fatheads: How neurons protect themselves against excess fat
We’re all fatheads. That is, our brain cells are packed with fat molecules, more of them than almost any other cell type. Still, if the brain cells’ fat content gets too high, they’ll be in trouble. In a recent study in mice, researchers at Johns Hopkins pinpointed an enzyme that keeps neurons’ fat levels under control, and may be implicated in human neurological diseases. Their findings are published in the May 2013 issue of Molecular and Cellular Biology.
"There are known connections between problems with how the body’s cells process fats and neurodegenerative diseases such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis," says Michael Wolfgang, Ph.D., an assistant professor in the Department of Biological Chemistry at the Johns Hopkins University School of Medicine’s Institute for Basic Biomedical Sciences. "Now we’ve taken a step toward better understanding that connection by identifying an enzyme that lets neurons get rid of excess fat that would otherwise be toxic."
Wolfgang says one clue to the reason for the neurodegeneration/fat-processing connection is that neurons, unlike most cells in the body, seemingly can’t break down fats for energy. Instead, brain cells use fats for tasks such as building cell membranes and communicating information. At the same time, he says, they must prevent the buildup of unneeded fats. Neurons’ fat-loss strategy is rooted in the fact that a fat molecule attached to a chemical group called coenzyme A will be trapped inside the cell, while the coenzyme A-free version can easily cross the cell membrane and escape. With this in mind, Wolfgang, along with colleagues Jessica Ellis, Ph.D., and G. William Wong, Ph.D., focused their study on an enzyme, called ACOT7, which is plentiful in the brain and lops coenzyme A off of certain fat molecules.
The team created mice with a non-working gene for ACOT7 and compared them with normal mice. The scientists saw no obvious differences between the two types of mice as long as they had ready access to food, Wolfgang says. But when food was taken away overnight, so that the mice’s cells would start to break down their fat stores and release fat molecules into the bloodstream for use as energy, ACOT7’s role began to emerge. While the normal fasting mice were merely hungry, the mice lacking ACOT7 had poor coordination, a sign of neurodegeneration. More differences emerged when the researchers dissected the mice; most strikingly, the livers of mice missing ACOT7 were “stark white” with excess fat, Wolfgang says.
Wolfgang cautions that his group’s results are not quite a smoking gun for ACOT7’s involvement in human neurological disease, but says they add to existing circumstantial evidence pointing in that direction. He notes that a special diet that changes the levels of fats and sugars in the bloodstream – the so-called ketogenic diet – can prevent seizures in epileptics; in addition, one study found that patients with epilepsy have less of the ACOT7 enzyme than healthy people.
"We think ACOT7’s purpose is to protect neurons from toxicity and death by allowing excess fat to escape the cells," Ellis says. "Our next step will be to see whether this enzyme does indeed play a role in human neurological disease."
(Image: Courtesy of Sabrina Diano)
Researchers Develop New System to Study Trigger of Cell Death in Nervous System
Researchers at the University of Arkansas have developed a new model system to study a receptor protein that controls cell death in both humans and fruit flies, a discovery that could lead to a better understanding of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Michael Lehmann, an associate professor of biological sciences, uses fruit fly genetics to study the receptor — N-methyl-D-aspartate receptor, known as the NMDA receptor — that triggers programmed cell death in the human nervous system.
With an aging population, neurodegenerative diseases have become a major public health concern, Lehmann said.
“Whenever brain cells die as a result of neurodegenerative disease, or as a consequence of injuries caused by stroke, exposure to alcohol or neurotoxins, this receptor is involved,” he said. “So it’s very important to understand how it functions and how it may be possible to influence it.”
When larvae of Drosophila melanogaster, a common fruit fly, grow from the larval stage into adults, they shed most of their former organs and grow new ones. About 1 ½ years ago, researchers in Lehmann’s laboratory discovered that the NMDA receptor is required for cell death in the system that they had used for several years to study basic mechanisms of programmed cell death in fruit flies.
“Our model system for studying programmed cell death is the salivary glands in the fly larvae, which are comparatively large organs that completely disappear during metamorphosis,” he said. “Disposal of this tissue by programmed cell death provides us with a very nice system to study the genes that are required for the process. We can use it to identify genes that are required for programmed cell death in humans, as well.”
The National Institutes of Health has awarded Lehmann a three-year, $260,530 grant to support the study.
Brandy Ree, a doctoral student in the interdisciplinary graduate program in cell and molecular biology, worked with Lehmann to use a combination of biochemistry and fruit fly genetics in an attempt to define the pathway that leads from activation of the receptor to the cell’s eventual death.
“We developed a new system to study the receptor outside the nervous system in a normal developmental context,” Lehmann said. “Many of the different components involved in cell death are known in this system. There are more than 30,000 publications about this receptor, but there is still very little known about how the receptor causes cell death. We just have to connect the dots and fit the receptor into the pathway to find out how exactly it contributes to the cell’s death.”
A mid-career investigator in the Center for Protein Structure and Function at the University of Arkansas, Lehmann has studied programmed cell death in Drosophila melanogaster for more than a decade.
In 2007, Lehmann’s research group discovered an important mechanism that regulates the destruction of larval fruit fly salivary glands that could point the way to understanding programmed cell death in the human immune system. They published their findings in the Journal of Cell Biology.
(Image: BD Biosciences)
Accused of complicity in Alzheimer’s, amyloid proteins may be getting a bad rap
Amyloids — clumps of misfolded proteins found in the brains of people with Alzheimer’s disease and other neurodegenerative disorders — are the quintessential bad boys of neurobiology. They’re thought to muck up the seamless workings of the neurons responsible for memory and movement, and researchers around the world have devoted themselves to devising ways of blocking their production or accumulation in humans.
But now a pair of recent research studies from the Stanford University School of Medicine sets a solid course toward rehabilitating the reputation of the proteins that form these amyloid tangles, or plaques. In the process, they appear poised to turn the field of neurobiology on its head.
The first study, published in August, showed that an amyloid-forming protein called beta amyloid, which is strongly implicated in Alzheimer’s disease, could reverse the symptoms of a multiple-sclerosis-like neurodegenerative disease in laboratory mice.
The second study, published April 3 in Science Translational Medicine, extends the finding to show that small portions of several notorious amyloid-forming proteins (including well-known culprits like tau and prion proteins) can also quickly alleviate symptoms in mice with the condition — despite the fact that the fragments can and do form the long tendrils, or fibrils, previously thought harmful to nerve health.
“What we’re finding is that, at least under certain circumstances, these amyloid peptides actually help the brain,” said Lawrence Steinman, MD, professor of neurology and neurological sciences and of pediatrics. “This really turns the ‘amyloid-is-bad’ dogma upside down. It will require a shift in people’s fundamental beliefs about neurodegeneration and diseases like multiple sclerosis, Alzheimer’s and Parkinson’s.”
Steinman is a noted expert in multiple sclerosis whose research led to the development of natalizumab (marketed as Tysabri), a potent treatment for the disease.
Taken together, the studies begin to suggest the radical new idea that full-length, amyloid-forming proteins may in fact be produced by the body as a protective, rather than destructive, force. In particular, Steinman’s study shows that these proteins may function as molecular chaperones, escorting and removing from sites of injury specific molecules involved in inflammation and inappropriate immune responses.
Steinman, who is also the medical school’s George A. Zimmermann Professor, is the corresponding author of the research. Jonathan Rothbard, PhD, a senior research scientist in the Steinman laboratory, is the senior author; postdoctoral scholar Michael Kurnellas, PhD, is the lead author.
Although the specific findings of Steinman’s two studies are surprising, there have been inklings from previous research that amyloid-forming proteins may not be all bad. In particular, inhibiting, or knocking out, the expression of several of the proteins in the mouse models of multiple sclerosis — a technique that should block the course of the disease if these proteins are the cause — instead worsened the animals’ symptoms.
And there’s the fact that these so-called dangerous amyloid-forming molecules are surprisingly prevalent. “We know the body makes a lot of amyloid-forming proteins in response to injury,” said Steinman. “I’m doubtful that that’s done to produce more harm. For example, the prion protein is found in every cell in our bodies. What is it doing? It’s possible that any therapeutic maneuver to remove all of these proteins could interfere with their natural function.”
Understanding how amyloids form requires an understanding of the biology of proteins, which are essentially strings of smaller components called amino acids attached end to end. Once they’re made, these protein strings twist and fold into specific three-dimensional shapes that fit together like keys and locks to do the work of the cell.
A misfolded protein is likely to be unable to carry out its duties and must be disposed of by the body’s cellular waste-management system. Amyloid-forming proteins (of which there are around 20), however, don’t go quietly, if at all. Instead, they initiate a chain reaction with other misfolded proteins — forming long, insoluble strands called fibrils that mat together to form amyloid clumps. These clumps appear consistently in the brains of people with neurodegenerative diseases like Alzheimer’s and multiple sclerosis, but not in the brains of healthy people.
Although these clumps are thought to be detrimental to nerve cells, it’s not entirely clear how they cause harm. One possibility is the ability of the fibrils to form cylindrical pores that could disrupt the cellular membrane and interfere with the orderly flow of ions and molecules used by the cells to communicate and transmit nerve signals. Regardless, their very presence suggests a diagnosis of neurodegeneration to many clinicians, including — until recently — Steinman.
“We began this research because these molecules are present in the brains of people with multiple sclerosis,” said Steinman. “We expected to show that the presence of beta amyloid made the disease worse in laboratory animals. Instead, we saw a great deal of benefit.”
Intrigued by the results of their first study, the researchers next tested the effect of small, six-amino-acid portions of several amyloid-forming proteins, including beta amyloid, which appeared likely to share a three-dimensional structure. They found that nearly all of the tiny protein molecules, or hexamers, were also able to temporarily reverse the symptoms of multiple sclerosis in the mice (when the treatment was stopped, the mice developed signs of the condition within a few days).
The researchers noted, however, that the curative effect of the hexamers was linked to their ability to form fibrils similar, but not identical, to their longer parent molecules. For example, these simplified hexamer fibrils are more easily formed and broken apart than those composed of whole proteins. They are also thought not to be able to form the cylindrical pores that might damage cell membranes. Finally, the hexamer fibrils appear to inhibit the formation of fibrils from full-length proteins — perhaps by blocking, or failing to promote, the chain reaction that initiates fibril formation.
When Steinman and his colleagues mixed the fibril-forming hexamers with blood plasma from three people with multiple sclerosis, they found that the fibrils bound to and removed from solution many potentially damaging molecules involved in inflammation and the immune response.
“These hexamer fibrils appear to be working to remove dangerous chemicals from the vicinity of the injury,” said Steinman.
The researchers are eager to pursue the use of these small hexamers as therapies for neurodegenerative diseases like multiple sclerosis. Much research is still needed, but Steinman is hopeful.
“The lessons we learn from our study of amyloid-forming proteins in multiple sclerosis could be helpful for stroke and brain trauma, as well as for Alzheimer’s,” said Steinman. “We’re gaining insight into how current therapeutic approaches may be affecting the body, and beginning to understand the nuances necessary to design a successful treatment. Although it will take time, we’re determined to move promising results out of the laboratory and into the clinic as quickly as possible.”
(Image: Wikimedia Commons)
BRAIN Initiative Launched to Unlock Mysteries of Human Mind
Today at the White House, President Barak Obama unveiled the “BRAIN” Initiative — a bold new research effort to revolutionize our understanding of the human mind and uncover new ways to treat, prevent, and cure brain disorders like Alzheimer’s, schizophrenia, autism, epilepsy, and traumatic brain injury.
The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is part of a new Presidential focus aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a revolutionary new dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space. Long desired by researchers seeking new ways to treat, cure, and even prevent brain disorders, this picture will fill major gaps in our current knowledge and provide unprecedented opportunities for exploring exactly how the brain enables the human body to record, process, utilize, store, and retrieve vast quantities of information, all at the speed of thought.
Why is the NIH BRAIN Initiative needed?
With nearly 100 billion neurons and 100 trillion connections, the human brain remains one of the greatest mysteries in science and one of the greatest challenges in medicine. Neurological and psychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, autism, epilepsy, schizophrenia, depression, and traumatic brain injury, exact a tremendous toll on individuals, families, and society. Despite the many advances in neuroscience in recent years, the underlying causes of most of neurological and psychiatric conditions remain largely unknown, due to the vast complexity of the human brain. If we are ever to develop effective ways of helping people suffering from these devastating conditions, researchers will first need a more complete arsenal of tools and information for understanding how the brain functions both in health and disease.
Why is now the right time for the NIH BRAIN Initiative?
In the last decade alone, scientists have made a number of landmark discoveries that now create the opportunity to unlock the mysteries of the brain. We have witnessed the sequencing of the human genome, the development of new tools for mapping neuronal connections, the increasing resolution of imaging technologies, and the explosion of nanoscience. These discoveries have yielded unprecedented opportunities for integration across scientific fields. For instance, by combining advanced genetic and optical techniques, scientists can now use pulses of light in animal models to determine how specific cell activities within the brain affect behavior. What’s more, through the integration of neuroscience and physics, researchers can now use high-resolution imaging technologies to observe how the brain is structurally and functionally connected in living humans.
While these technological innovations have contributed substantially to our expanding knowledge of the brain, significant breakthroughs in how we treat neurological and psychiatric disease will require a new generation of tools to enable researchers to record signals from brain cells in much greater numbers and at even faster speeds. This cannot currently be achieved, but great promise for developing such technologies lies at the intersections of nanoscience, imaging, engineering, informatics, and other rapidly emerging fields of science.
How will the NIH BRAIN Initiative work?
Given the ambitious scope of this pioneering endeavor, it is vital that planning for the NIH BRAIN Initiative be informed by a wide range of expertise and experience. Therefore, NIH is establishing a high level working group of the Advisory Committee to the NIH Director (ACD) to help shape this new initiative. This working group, co-chaired by Dr. Cornelia “Cori” Bargmann (The Rockefeller University) and Dr. William Newsome (Stanford University), is being asked to articulate the scientific goals of the BRAIN initiative and develop a multi-year scientific plan for achieving these goals, including timetables, milestones, and cost estimates.
As part of this planning process, input will be sought broadly from the scientific community, patient advocates, and the general public. The working group will be asked to produce an interim report by fall 2013 that will contain specific recommendations on high priority investments for Fiscal Year (FY) 2014. The final report will be delivered to the NIH Director in June 2014.
How will the NIH BRAIN Initiative be supported?
In total, NIH intends to allocate $40 million in FY14. Given the cross-cutting nature of this project, the NIH Blueprint for Neuroscience Research — an initiative spanning 14 NIH Institutes and Centers — will be the leading NIH contributor to its implementation in FY14. Of course, a goal this audacious will require ideas from the best scientists and engineers across many diverse disciplines and sectors. Therefore, NIH is working in close collaboration with other government agencies, including the Defense Advanced Research Projects Agency (DARPA) and the National Science Foundation (NSF). Strong interest has also been expressed by several private foundations, including the Howard Hughes Medical Institute, the Allen Institute for Brain Science, and The Kavli Foundation, and the Salk Institute for Biological Studies. Private industries have also expressed a high level of interest in participation in this groundbreaking initiative.
Obama proposes $100m to map the human brain
President Barack Obama on Tuesday asked Congress to spend $100 million next year on a new project to map the human brain in hopes of eventually finding cures for disorders like Alzheimer’s, epilepsy and traumatic injuries.
Obama said the so-called BRAIN Initiative could create jobs and eventually lead to answers to ailments including Parkinson’s and autism and help reverse the effect of a stroke. The president told scientists gathered in the White House’s East Room that the research has the potential to improve the lives of billions of people worldwide.
‘‘As humans we can identify galaxies light-years away,’’ Obama said. ‘‘We can study particles smaller than an atom, but we still haven’t unlocked the mystery of the three pounds of matter that sits between our ears.’’
BRAIN stands for Brain Research through Advancing Innovative Neurotechnologies. The idea, which Obama first proposed in his State of the Union address, would require the development of new technology that can record the electrical activity of individual cells and complex neural circuits in the brain ‘‘at the speed of thought,’’ the White House said.
Obama wants the initial $100 million investment to support research at the National Institutes of Health, the Defense Advanced Research Projects Agency and the National Science Foundation. He also wants private companies, universities and philanthropists to partner with the federal agencies in support of the research. And he wants a study of the ethical, legal and societal implications of the research.
The goals of the work are unclear at this point. A working group at NIH, co-chaired by Cornelia ‘‘Cori’’ Bargmann of The Rockefeller University and William Newsome of Stanford University, would work on defining the goals and develop a multi-year plan to achieve them that included cost estimates.
Scientists develop 3-D stem cell culture technique to better understand Alzheimer’s disease
A team of researchers at The New York Stem Cell Foundation Research Institute led by Scott Noggle, PhD, Director of the NYSCF Laboratory and the NYSCF – Charles Evans Senior Research Fellow for Alzheimer’s Disease, and Michael W. Nestor, PhD, a NYSCF Postdoctoral Research Fellow, has developed a technique to produce three-dimensional cultures of induced pluripotent stem (iPS) cells called embryoid bodies, amenable to live cell imaging and to electrical activity measurement. As reported in their Stem Cell Research study, these cell aggregates enable scientists to both model and to study diseases such as Alzheimer’s and Parkinson’s disease.
The NYSCF Alzheimer’s disease research team aims to better understand and to find treatments to this disease through stem cell research. For such disorders in which neurons misfire or degenerate, the NYSCF team creates “disease in a dish” models by reprogramming patients’ skin and or blood samples into induced pluripotent stem (iPS) cells that can become neurons and the other brain cells affected in the diseases.
The cells in our body form three-dimensional networks, essential to tissue function and overall health; however, previous techniques to form complex brain tissue resulted in structures that, while similar in form to naturally occurring neurons, undermined imaging or electrical recording attempts.
In the current study, the Noggle and Nestor with NYSCF scientists specially adapted two-dimensional culture methods to grow three-dimensional neuron structures from iPS cells. The resultant neurons were “thinned-out,” enabling calcium-imaging studies, which measure the electrical activity of cells like neurons.
"Combining the advantages of iPS cells grown in a 3D environment with those of a 2D system, our technique produces cells that can be used to observe electrical activity of putative networks of biologically active neurons, while simultaneously imaging them," said Nestor. "This is key to modeling and studying neurodegenerative diseases."
Neural networks, thought to underlie learning and memory, become disrupted in Alzheimer’s disease. By generating aggregates from iPS cells and comparing these to an actual patient’s brain tissue, scientists may uncover how disease interferes with these cell-to-cell interactions and understand how to intervene to slow or stop Alzheimer’s disease.
"This critical new tool developed by our Alzheimer’s team will accelerate Alzheimer’s research, enabling more accurate manipulation of cells to find a cure to this disease," said Susan L. Solomon, CEO of NYSCF.
(Source: eurekalert.org)
Sorting out the structure of a Parkinson’s protein
Clumps of proteins that accumulate in brain cells are a hallmark of neurological diseases such as dementia, Parkinson’s disease and Alzheimer’s disease. Over the past several years, there has been much controversy over the structure of one of those proteins, known as alpha synuclein.
MIT computational scientists have now modeled the structure of that protein, most commonly associated with Parkinson’s, and found that it can take on either of two proposed states — floppy or rigid. The findings suggest that forcing the protein to switch to the rigid structure, which does not aggregate, could offer a new way to treat Parkinson’s, says Collin Stultz, an associate professor of electrical engineering and computer science at MIT.
“If alpha synuclein can really adopt this ordered structure that does not aggregate, you could imagine a drug-design strategy that stabilizes these ordered structures to prevent them from aggregating,” says Stultz, who is the senior author of a paper describing the findings in a recent issue of the Journal of the American Chemical Society.
For decades, scientists have believed that alpha synuclein, which forms clumps known as Lewy bodies in brain cells and other neurons, is inherently disordered and floppy. However, in 2011 Harvard University neurologist Dennis Selkoe and colleagues reported that after carefully extracting alpha synuclein from cells, they found it to have a very well-defined, folded structure.
That surprising finding set off a scientific controversy. Some tried and failed to replicate the finding, but scientists at Brandeis University, led by Thomas Pochapsky and Gregory Petsko, also found folded (or ordered) structures in the alpha synuclein protein.
Stultz and his group decided to jump into the fray, working with Pochapsky’s lab, and developed a computer-modeling approach to predict what kind of structures the protein might take. Working with the structural data obtained by the Brandeis researchers, Stultz created a model that calculates the probabilities of many different possible structures, to determine what set of structures would best explain the experimental data.
The calculations suggest that the protein can rapidly switch among many different conformations. At any given time, about 70 percent of individual proteins will be in one of the many possible disordered states, which exist as single molecules of the alpha synuclein protein. When three or four of the proteins join together, they can assume a mix of possible rigid structures, including helices and beta strands (protein chains that can link together to form sheets).
“On the one hand, the people who say it’s disordered are right, because a majority of the protein is disordered,” Stultz says. “And the people who would say that it’s ordered are not wrong; it’s just a very small fraction of the protein that is ordered.”
“This paper seems to bridge the gap” between the two camps, says Trevor Creamer, an associate professor of molecular and cellular biochemistry at the University of Kentucky who was not involved in this research. Also important is the model’s prediction of new structures for the protein that experimental biologists can now look for, Creamer adds.
The MIT researchers also found that when alpha synuclein adopts an ordered structure, similar to that described by Selkoe and co-workers, the portions of the protein that tend to aggregate with other molecules are buried deep within the structure, explaining why those ordered forms do not clump together.
Stultz is now working to figure out what controls the protein’s configuration. There is some evidence that other molecules in the cell can modify alpha synuclein, forcing it to assume one conformation or another.
“If this structure really does exist, we have a new way now of potentially designing drugs that will prevent aggregation of alpha synuclein,” he says.
(Source: web.mit.edu)
Parkinson’s Disease Protein Gums up Garbage Disposal System in Cells
Clumps of α-synuclein protein in nerve cells are hallmarks of many degenerative brain diseases, most notably Parkinson’s disease.
“No one has been able to determine if Lewy bodies and Lewy neurites, hallmark pathologies in Parkinson’s disease can be degraded,” says Virginia Lee, PhD, director of the Center for Neurodegenerative Disease Research, at the Perelman School of Medicine, University of Pennsylvania.
“With the new neuron model system of Parkinson’s disease pathologies our lab has developed recently, we demonstrated that these aberrant clumps in cells resist degradation as well as impair the function of the macroautophagy system, one of the major garbage disposal systems within the cell.”
Macroautophagy, literally self eating, is the degradation of unnecessary or dysfunctional cellular bits and pieces by a compartment in the cell called the lysosome.
Lee, also a professor of Pathology and Laboratory Medicine, and colleagues published their results in the early online edition of the Journal of Biological Chemistry this week.
Alpha-synuclein (α-syn ) diseases all have clumps of the protein and include Parkinson’s disease (PD), and array of related disorders: PD with dementia , dementia with Lewy bodies, and multiple system atrophy. In most of these, α-syn forms insoluble aggregates of stringy fibrils that accumulate in the cell body and extensions of neurons.
These unwanted α-syn clumps are modified by abnormal attachments of many phosphate chemical groups as well as by the protein ubiquitin, a molecular tag for degradation. They are widely distributed in the central nervous system, where they are associated with neuron loss.
Using cell models in which intracellular α-syn clumps accumulate after taking up synthetic α-syn fibrils, the team showed that α-syn inclusions cannot be degraded, even though they are located near the lysosome and the proteasome, another type of garbage disposal in the cell.
The α-syn aggregates persist even after soluble α-syn levels within the cell are substantially reduced, suggesting that once formed, the α-syn inclusions are resistant to being cleared. What’s more, they found that α-syn aggregates impair the overall autophagy degradative process by delaying the maturation of autophagy machines known as autophagosomes, which may contribute to the increased cell death seen in clump-filled nerve cells. Understanding the impact of α-syn aggregates on autophagy may help elucidate therapies for α-syn-related neurodegeneration.
(Source: uphs.upenn.edu)