Posts tagged brain cells
Articles and news from the latest research reports.
Researchers discover novel function of protein linked to Alzheimer’s disease
A research team led by the National Neuroscience Institute (NNI) has uncovered a novel function of the Amyloid Precursor Protein (APP), one of the main pathogenic culprits of Alzheimer’s disease. This discovery may help researchers understand how the protein goes awry in the brains of Alzheimer’s disease patients, and potentially paves the way for the development of innovative therapeutics to improve the brain function of dementia patients.
The findings were published in the prestigious scientific research journal Nature Communications last month. The study, which is led by Dr Zeng Li and her team from NNI, involved investigators from Duke-NUS Graduate Medical School and the Agency for Science and Technology (A*STAR).
Alzheimer’s disease is the most common form of dementia, which is set to rise significantly from the current 28,000 cases to 80,000 cases in 2030 among Singaporeans aged 60 and above. With a rapidly aging population, the burden of the disease will be profound affecting not just the person afflicted, but also the caregiver and family. While the exact cause of Alzheimer’s disease remains unknown, one of its pathological hallmarks is clear – the clumping of APP product in the brain when the protein is abnormally processed.
Finding out more about APP can help researchers gain a better understanding of the disease, and potentially identify biomarkers and therapeutic targets for it. However up till this point, little was known about the APP’s primary function in the brain.
(Source: eurekalert.org)
Brain cell find points to new therapies
Insights into how brain cells are produced could lead to treatments for brain cancer and other brain-related disorders.
Scientists have gained new understanding of the role played by a key molecule that controls how and when nerve and brain cells are formed - a process that allows the brain to develop and keeps it healthy.
Their findings could help explain what happens when cell production goes out of control, which is a fundamental characteristic of many diseases including cancer.
Regulatory systems
Researchers have focused on a RNA molecule, known as miR-9, which is linked to the development of brain cells, known as neurons and glial cells.
They have shown that a protein called Lin28a regulates the production of miR-9, which in turn controls the genes involved in brain cell development and function.
Scientists carried out lab studies of embryonic cells, which can develop into neurons, to determine how Lin28a controls the amount of miR-9 that is produced.
Complex pathways
They found that in embryonic cells, Lin28a prevents production of miR-9 by triggering the degradation of its precursor molecule.
In developed brain cells, Lin28a is no longer produced, which enables miR-9 to accumulate and function.
In cancer cells, Lin28a production is re-established, and as a result this natural process is disrupted.
Lab experiments
Researchers used a series of lab tests to unravel the complex processes that are directed by the Lin28a protein.
They say further studies could help explain fully the role of Lin28a and miR-9 in brain development, and pave the way to the development of novel therapies.
The study, published in Nature Communications, was supported by the Wellcome Trust and the Medical Research Council.
Understanding more of the complex science behind the fundamental processes of cell development will helps us learn more about what happens when this goes wrong – and what might be done to prevent it. -Dr Gracjan Michlewski (School of Biological Sciences)
(Image: iStock)
Researchers search for earliest roots of psychiatric disorders
Newborns whose mothers were exposed during pregnancy to any one of a variety of environmental stressors — such as trauma, illness, and alcohol or drug abuse — become susceptible to various psychiatric disorders that frequently arise later in life. However, it has been unclear how these stressors affect the cells of the developing brain prenatally and give rise to conditions such as schizophrenia, post-traumatic stress disorder, and some forms of autism and bipolar disorders.
Now, Yale University researchers have identified a single molecular mechanism in the developing brain that sheds light on how cells may go awry when exposed to a variety of different environmental insults. The findings, to be published in the May 7 issue of the journal Neuron, suggest that different types of stressors prenatally activate a single molecular trigger in brain cells that may make exposed individuals susceptible to late-onset neuropsychiatric disorders.
The researchers found that mouse embryos exposed to alcohol, methyl-mercury, or maternal seizures all activate in the developing brain cells a single gene — HSF1 or heat shock factor — which protects and enables some of the brain cells to survive prenatal insult. Mice lacking the HSF1 gene showed structural brain abnormalities and were prone to seizures after birth, even after exposure to very low levels of the toxins.
In addition, researchers created stem cells — which are capable of becoming many different tissue types, including neurons — from biopsies of individuals diagnosed with schizophrenia. Genes from these “schizophrenic” stem cells responded more dramatically when exposed to environmental insults than stem cells obtained from non-schizophrenic individuals. The findings provide support to the thesis that stress induces vulnerable cells to malfunction.
“It appears that different types of environmental stressors can trigger the same condition if they occur at the same period of prenatal development,” said Yale’s Pasko Rakic, senior author of the study. “Conversely, the same environmental stressor may cause different pathologies, if it occurs at different times during pregnancy.”
Since HSF1 activation can potentially serve as a permanent marker of the stressed/damaged cell, it opens the possibility of identifying these cells in adults in order to explore the pathogenesis of postnatal disorders and how to protect vulnerable cells.
Most land animals walk forward by default, but can switch to backward walking when they sense an obstacle or danger in the path ahead. The impulse to change walking direction is likely to be transmitted by descending neurons of the brain that control local motor circuits within the central nervous system. This neuronal input can change walking direction by adjusting the order or timing of individual leg movements.
Screening for flies with altered walking patterns
In the current study, Dickson and his team aimed to understand the fly’s change in walking direction at the cellular level. Using a novel technology known as thermogenetics, they were able to identify the neurons in the brain that cause a change in locomotion. Their studies involved screening large numbers of flies with it which specific neurons were activated by heat, producing certain behaviors only when warmed to 30°C, but not at 24°C . Analysing several thousand flies, the researchers looked for strains that exhibited altered walking patterns compared to control animals.
Moonwalker-neurons control backward walking
Using the thermogenetic screen, the IMP-researchers isolated four lines of flies that walked backward on heat activation. They were able to track down these changes to specific nerve cells in the fly brain which they dubbed “moonwalker neurons”. They could also show that silencing the activity of these neurons using tetanus toxin rendered the flies unable to walk backward.
Among the moonwalker neurons, the activity of descending MDN-neurons is required for flies to walk backward when they encounter an obstacle. Input from MDN brain cells is sufficient to induce backward walking in flies that would otherwise walk forward. Ascending moonwalker neurons (MAN) promote persistent backward walking, possibly by inhibiting forward walking.
“This is the first identification of specific neurons that carry the command for the switch in walking direction of an insect”, says Salil Bidaye, lead author of the study. “Our findings provide a great entry point into the entire walking circuit of the fly. “
Although there are obvious differences in how insects and humans walk, it is likely that there are functional analogies at a neural circuit level. Insights into the neural basis of insect walking could also generate applications in the field of robotics. To date, none of the engineered robots that are used for rescue or exploration missions can walk as robustly as animals. Understanding how insects change their walking direction at a neuronal level would reveal the mechanistic basis of achieving such robust walking behavior.
New clue to autism found inside brain cells
The problems people with autism have with memory formation, higher-level thinking and social interactions may be partially attributable to the activity of receptors inside brain cells, researchers at Washington University School of Medicine in St. Louis have learned.
(Image caption: Learning, social interactions and higher-level thinking in people with autism may be adversely affected by receptors inside brain cells, scientists at Washington University School of Medicine have learned. The type of receptor they studied glows green on the surface of this cell. Inside the cell, the receptor covers a membrane stained red. Credit: Yuh-Jiin I. Jong)
Scientists were already aware that the type of receptor in question was a potential contributor to these problems – when located on the surfaces of brain cells. Until now, though, the role of the same type of receptor located inside the cell had gone unrecognized. Such receptors inside cells significantly outnumber the same type of receptors on the surface of cells.
The receptor under study, known as the mGlu5 receptor, becomes activated when it binds to the neurotransmitter glutamate, which is associated with learning and memory. This leads to chain reactions that convert the glutamate’s signal into messages traveling inside the cell.
In the new study, scientists working with cells in a dish linked mGlu5 receptors inside cells to processes that turn down the volume at which brain cells talk to each other. These volume changes, essential for learning and memory, may become exaggerated in people with autism.
Pharmaceutical companies have developed therapeutic compounds to decrease signaling associated with the mGlu5 receptor, moderating its effects on brain cells’ volume knobs. But the compounds were designed to target mGlu5 surface receptors. In light of the new findings, the scientists question if those drugs will reach the receptors inside cells.
“Our results suggest that to have the greatest therapeutic benefit, we may need to make sure we’re blocking all of this type of receptor, both inside and on the surface of the cell,” said senior investigator Karen O’Malley, PhD, professor of neurobiology.
The findings, published March 25 in The Journal of Neuroscience, also add a significant new dimension to basic brain cell function. Scientists have long assumed that brain cell receptors are only active on the surface of cells. The new study shows that receptors can be active inside cells, and their effects can be considerably different from the same receptors located on the cell surface.
“The traditional wisdom was that receptors inside the cell were either waiting to go to work on the surface or had just finished working there,” said O’Malley. “But when we compared how much of the mGlu5 receptor was on the surface of cells to how much was inside it, we were seeing so much more receptor inside the cell – at least 50 percent, and in some cases as much as 90 percent – that we wondered if the interior receptors had separate functions.”
In earlier studies, O’Malley and her collaborators showed that mGlu5 receptors on the cell surface sent completely different messages than the same receptors inside the cell.
The scientists knew that most autism studies were conducted with compounds that blocked mGlu5 receptors but could not get into the cell. To determine whether blocking inside receptors would have different effects, O’Malley collaborated with Yukitoshi Izumi, MD, PhD, research professor of psychiatry, and Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry, who study cell-based models of learning and memory.
When the scientists examined these model systems using compounds that allowed them to activate only mGlu5 receptors within cells, they found that these receptors played a bigger role in turning down the volume of brain cell communications than did the cell surface receptors.
In the last few years, scientists have found that 20 or more types of brain cell receptors located on cell surfaces also are present at high levels inside cells, O’Malley noted.
“This should be a factor we consider when we design drugs to target brain cell receptors,” she said. “Do we want to reach cell surface receptors, receptors inside the cell or both?”
(Source: news.wustl.edu)
Halting Immune Response Could Save Brain Cells After Stroke
A new study in animals shows that using a compound to block the body’s immune response greatly reduces disability after a stroke.
The study by scientists from the University of Wisconsin School of Medicine and Public Health also showed that particular immune cells – CD4+ T-cells produce a mediator, called interleukin (IL)-21 that can cause further damage in stroke tissue.
Moreover, normal mice, ordinarily killed or disabled by an ischemic stroke, were given a shot of a compound that blocks the action of IL-21. Brain scans and brain sections showed that the treated mice suffered little or no stroke damage.
“This is very exciting because we haven’t had a new drug for stroke in decades, and this suggests a target for such a drug,” says lead author Dr. Zsuzsanna Fabry, professor of pathology and laboratory medicine
Stroke is the fourth-leading killer in the world and an important cause of permanent disability. In an ischemic stroke, a clot blocks the flow of oxygen-rich blood to the brain. But Fabry explains that much of the damage to brain cells occurs after the clot is removed or dissolved by medicine. Blood rushes back into the brain tissue, bringing with it immune cells called T-cells, which flock to the source of an injury.
The study shows that after a stroke, the injured brain cells provoke the CD4+ T-cells to produce a substance, IL-21, that kills the neurons in the blood-deprived tissue of the brain. The study gave new insight how stroke induces neural injury.
Similar Findings in Humans
Fabry’s co-author Dr. Matyas Sandor, professor of pathology and laboratory medicine, says that the final part of the study looked at brain tissue from people who had died following ischemic strokes. It found that CD4+ T-cells and their protein, IL-21 are in high concentration in areas of the brain damaged by the stroke.
Sandor says the similarity suggests that the protein that blocks IL-21 could become a treatment for stroke, and would likely be administered at the same time as the current blood-clot dissolving drugs.
“We don’t have proof that it will work in humans,” he says, “but similar accumulation of IL-21 producing cells suggests that it might.”
The paper was published this week in the Journal of Experimental Medicine.
(Source: med.wisc.edu)
Environmentally sensitive cells with a Hulk-like rage
Human exposure to urban air pollution may trigger toxic responses in brain cells and impact neurodegenerative disease pathways
From diesel exhaust to gaseous pollutants and suspended particulate matter, such as dust, smoke and fumes, air pollution from transportation, industry and energy generation has taken a toll on the environment and human health.
While the adverse effects of air pollution on the cardiovascular and respiratory systems have been well documented, little is known about how the associated toxins may impact the brain and the central nervous system. In recent years, experts have reported a marked rise in the prevalence of stroke, autism and cognitive decline in the elderly.
Researchers such as Michelle Block, Ph.D., associate professor in the Department of Anatomy and Neurobiology in the Virginia Commonwealth University School of Medicine, are now on a mission to define the impact of air pollution on the brain and central nervous system.
Through basic science, Block and her team are working to understand the underlying molecular mechanisms in hopes of developing an intervention that can protect human health.
Recent scientific reports suggest air pollution exposure and the activation of a specific group of cells found in the brain being studied in Block’s laboratory may play a role in the increased incidence of central nervous system diseases and neurological conditions. They have observed that these factors may also impact the neurodegenerative disease process.
Last week, Block, presented her team’s significant research findings to peers from across the country during a symposium she co-organized at the 2014 annual meeting of the American Association for the Advancement of Science, held in Chicago, from Feb. 13 to 17.
“Angry” cells, toxic responses
Block’s research examines microglia, a group of resident immune cells found in the brain and spinal cord, which can display a kind of dual personality – one good, and the other bad if agitated.
Under normal conditions, microglia primarily serve as the defenders of the central nervous system. They bring balance to the system. They destroy infectious agents, engulf various unwanted cellular and foreign materials and promote regrowth of damaged neural tissue.
But microglia can be dangerous when they are exceptionally “angry” and are known to leave behind significant bystander damage to neighboring cells. This adverse behavior may lead to the development of any number of neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, or Gulf War Illness.
In some ways, microglia are similar to misunderstood superhero The Incredible Hulk. Despite having a decent-sized heart and extraordinary abilities to help save the day, nobody wants to stir his rage and anger.
Block’s laboratory specializes in understanding the cellular and molecular machinery responsible for essentially fueling microglia “anger” – why they become chronically and excessively activated to drive damage in the brain.
“Our goal is to define how microglia detect and respond to air pollution, reveal when this microglial response may actually be damaging the brain, identify potential markers of ongoing silent neuropathology and ultimately use the mechanistic information we acquire as a tool to halt the induced or augmented neuropathology,” Block said.
In several peer-reviewed, published reports, Block and her colleagues have demonstrated that exposure to a diverse source of urban air pollution can trigger toxic microglial responses and impact neurodegenerative disease pathways.
“Given the prevalence of human exposure to urban air pollution above safety regulations, it is critical to understand the underlying mechanisms through which air pollution affects the brain,” Block said. “We hope to find an opportunity to intervene and protect human central nervous system health.”
According to Block, her team’s work shows that many components of urban air pollution, including the particle components of air pollution, also called particulate matter, and gases, such as ground level ozone, activate microglia.
Some of the problems with this cell type come in when the same molecular tools used by microglia internalize (eat) and clean up toxic stimuli and accidentally trigger the switch to an excessive, angry activation state. The work she presented reveals how air pollution does this, essentially leaving microglia with much more than a mouthful. Her lab has discovered that the MAC1 pattern recognition receptor may be a common mechanism through which microglia detect and ultimately misinterpret different forms of air pollution as an invading pathogen to result in excessive production of reactive oxygen species and consequent damage to neighboring brain cells.
Further, ongoing research in Block’s lab aims to define where damage to the lungs through inhaled toxicants produces injury signals in the circulation that are not only detected by microglia in the brain, but are responsible for shifting microglia to a deleterious phenotype impacting central nervous system health. She refers to this as a “Lung-Brain Axis.”
Scientists identify gene linking brain structure to intelligence
For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study is published today in Molecular Psychiatry and may help scientists understand biological mechanisms behind some forms of intellectual impairment.
The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified.
An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence.
Dr Sylvane Desrivières, from the MRC Social, Genetic and Developmental Psychiatry Centre at King’s College London’s Institute of Psychiatry and lead author of the study, said: “We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity – how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.”
She adds: “It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.”
The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate.
To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. The researchers found that the NPTN gene had a different activity in the left and right hemispheres of the brain, which may cause the left hemisphere to be more sensitive to the effects of NPTN mutations. Their findings suggest that some differences in intellectual abilities can result from the decreased function of the NPTN gene in particular regions of the left brain hemisphere.
The genetic variation identified in this study only accounts for an estimated 0.5% of the total variation in intelligence. However, the findings may have important implications for the understanding of biological mechanisms underlying several psychiatric disorders, such as schizophrenia, autism, where impaired cognitive ability is a key feature of the disorder.
(Source: kcl.ac.uk)
Optogenetic toolkit goes multicolor
Optogenetics is a technique that allows scientists to control neurons’ electrical activity with light by engineering them to express light-sensitive proteins. Within the past decade, it has become a very powerful tool for discovering the functions of different types of cells in the brain.
Most of these light-sensitive proteins, known as opsins, respond to light in the blue-green range. Now, a team led by MIT has discovered an opsin that is sensitive to red light, which allows researchers to independently control the activity of two populations of neurons at once, enabling much more complex studies of brain function.
“If you want to see how two different sets of cells interact, or how two populations of the same cell compete against each other, you need to be able to activate those populations independently,” says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT and a senior author of the new study.
The new opsin is one of about 60 light-sensitive proteins found in a screen of 120 species of algae. The study, which appears in the Feb. 9 online edition of Nature Methods, also yielded the fastest opsin, enabling researchers to study neuron activity patterns with millisecond timescale precision.
Boyden and Gane Ka-Shu Wong, a professor of medicine and biological sciences at the University of Alberta, are the paper’s senior authors, and the lead author is MIT postdoc Nathan Klapoetke. Researchers from the Howard Hughes Medical Institute’s Janelia Farm Research Campus, the University of Pennsylvania, the University of Cologne, and the Beijing Genomics Institute also contributed to the study.
Head first: reshaping how traumatic brain injury is treated
Traumatic brain injury affects 10 million people a year worldwide and is the leading cause of death and disability in children and young adults. A new study will identify how to match treatments to patients, to achieve the best possible outcome for recovery.
The human brain – despite being encased snugly within its protective skull – is terrifyingly vulnerable to traumatic injury. A severe blow to the head can set in train a series of events that continue to play out for months, years and even decades ahead. First, there is bleeding, clotting and bruising at the site of impact. If the blow is forceful enough, the brain is thrust against the far side of the skull, where bony ridges cause blood vessels to lacerate. Sliding of grey matter over white matter can irreparably shear nerve fibres, causing damage that has physical, cognitive and behavioural consequences. As response mechanisms activate, the brain then swells, increasing intracranial pressure, and closing down parts of the microcirculatory network, reducing the passage of oxygen from blood vessels into the tissues, and causing further tissue injury.
It is the global nature of the damage – involving many parts of the brain – that defines these types of traumatic brain injuries (TBIs), which might result from transport accidents, assaults, falls or sporting injuries. Unfortunately, both the pattern of damage and the eventual outcome are extremely variable from patient to patient.
“This variability has meant that TBI is often considered as the most complex disease in our most complex organ,” said Professor David Menon, Co-Chair of the Acute Brain Injury Programme at the University of Cambridge. “Despite advances in care, the sad truth is that we are no closer to knowing how to navigate past this variability to the point where we can link the particular characteristics of a TBI to the best treatment and outcome.”
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