Posts tagged microglia cells
Articles and news from the latest research reports.
Turmeric compound boosts regeneration of brain stem cells
A bioactive compound found in turmeric promotes stem cell proliferation and differentiation in the brain, reveals new research published today in the open access journal Stem Cell Research & Therapy. The findings suggest aromatic turmerone could be a future drug candidate for treating neurological disorders, such as stroke and Alzheimer’s disease.
The study looked at the effects of aromatic (ar-) turmerone on endogenous neutral stem cells (NSC), which are stem cells found within adult brains. NSC differentiate into neurons, and play an important role in self-repair and recovery of brain function in neurodegenerative diseases. Previous studies of ar-turmerone have shown that the compound can block activation of microglia cells. When activated, these cells cause neuroinflammation, which is associated with different neurological disorders. However, ar-turmerone’s impact on the brain’s capacity to self-repair was unknown.
Researchers from the Institute of Neuroscience and Medicine in Jülich, Germany, studied the effects of ar-turmerone on NSC proliferation and differentiation both in vitro and in vivo. Rat fetal NSC were cultured and grown in six different concentrations of ar-turmerone over a 72 hour period. At certain concentrations, ar-turmerone was shown to increase NSC proliferation by up to 80%, without having any impact on cell death. The cell differentiation process also accelerated in ar-turmerone-treated cells compared to untreated control cells.
To test the effects of ar-turmerone on NSC in vivo, the researchers injected adult rats with ar-turmerone. Using PET imaging and a tracer to detect proliferating cells, they found that the subventricular zone (SVZ) was wider, and the hippocampus expanded, in the brains of rats injected with ar-turmerone than in control animals. The SVZ and hippocampus are the two sites in adult mammalian brains where neurogenesis, the growth of neurons, is known to occur.
Lead author of the study, Adele Rueger, said: “While several substances have been described to promote stem cell proliferation in the brain, fewer drugs additionally promote the differentiation of stem cells into neurons, which constitutes a major goal in regenerative medicine. Our findings on aromatic turmerone take us one step closer to achieving this goal.”
Ar-turmerone is the lesser-studied of two major bioactive compounds found in turmeric. The other compound is curcumin, which is well known for its anti-inflammatory and neuroprotective properties.
Scientists catch brain damage in the act
Scientists have uncovered how inflammation and lack of oxygen conspire to cause brain damage in conditions such as stroke and Alzheimer’s disease.
The discovery, published today in Neuron, brings researchers a step closer to finding potential targets to treat neurodegenerative disorders.
Chronic inflammation and hypoxia, or oxygen deficiency, are hallmarks of several brain diseases, but little was known about how they contribute to symptoms such as memory loss.
The study used state-of-the-art techniques that reveal the movements of microglia, the brain’s resident immune cells. Brain researcher Brian MacVicar had previously captured how they moved to areas of injury to repair brain damage.
The new study shows that the combination of inflammation and hypoxia activates microglia in a way that persistently weakens the connection between neurons. The phenomenon, known as long-term depression, has been shown to contribute to cognitive impairment in Alzheimer’s disease.
“This is a never-before-seen mechanism among three key players in the brain that interact together in neurodegenerative disorders,” says MacVicar with the Djavad Mowafaghian Centre for Brain Health at UBC and Vancouver Coastal Health Research Institute.
“Now we can use this knowledge to start identifying new potential targets for therapy.”
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.”
Microglia Can Be Derived From Patient-Specific Human Induced Pluripotent Stem Cells and May Help Modulate the Course of Central Nervous System Diseases
Today, during the 81st American Association of Neurological Surgeons (AANS) Annual Scientific Meeting, researchers announced new findings regarding the development of methods to turn human induced pluripotent stem cells (iPSC) into microglia, which could be used for not only research but potentially in treatments for various diseases of the central nervous system (CNS).
Microglia are the resident inflammatory cells of the CNS and can modulate the outcomes of a wide range of disorders including trauma, infections, stroke, brain tumors, and various degenerative, inflammatory and psychiatric diseases. However, the effective therapeutic use of microglia demonstrated in various animal CNS disease models currently cannot be translated to patients due to the lack of methods for procuring high-purity patient-specific microglia. Developing a method for obtaining these cells would be highly valuable.
In the study Differentiation of Induced Pluripotent Stem Cells to Microglia for Treatment of CNS Diseases, mouse and human iPSCs were generated and sequentially co-cultured on various cell monolayers and in the presence of added growth factors. The microglial identity of the resulting cells was confirmed using fluorescence activated cell sorting analyses, functional assays, gene expression analyses and brain engraftment ability. The study results will be shared by presenting author John K. Park, MD, PhD, FAANS, from 3:34-3:42 p.m. on Monday, April 29. Co-authors are Michael Shen, BS; Yong Choi, PhD; and Hetal Pandya, PhD.
In the results, researchers found mouse and human iPSCs co-cultured with OP9 cells differentiate into hematopoietic progenitor cells (HPCs). HPCs in turn co-cultured with astrocytes, generate cells that express CD11b, Iba-1 and CX3CR1; secrete the cytokines IL-6, IL-1ß and TNF-a; generate reactive oxygen species; and phagocytose fluorescent particles, all consistent with a microglial phenotype. Gene expression clustering using self-organizing maps indicates that iPSC-derived microglia more closely resemble normal microglia than other inflammatory cell types. The iPSC-derived microglia engraft and migrate to areas of injury within the brain. These finding have led researchers to conclude that iPSC-derived microglia may one day be useful as gene and protein delivery vehicles to the CNS.
“The actual results of our research were not surprising to us, but the overall importance of microglia in a wide variety of brain and spinal cord diseases was surprising. Microglia likely have a role in improving or worsening diseases such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, obsessive compulsive disorder and Rett’s syndrome, just to name a few,” said John K. Park, MD, PhD, FAANS. “Microglia are the principal immune system cells of the brain and spinal cord, and help fight infections as well as help the healing process after injuries such as trauma and strokes. They also play a poorly understood role in many neurodegenerative and psychiatric diseases. We have developed methods to turn iPSCs into microglia. Because human iPSC can easily be obtained in large numbers, we can now generate large numbers of human microglia not only for use in experiments, but also potentially for use in treatments. The ability to study normal and diseased human microglia will lead to a greater understanding of their roles in healthy brains and various diseases. Diseases that are caused or exacerbated by defective microglia or a paucity of normal microglia may potentially be treated by microglia generated from a patient’s iPSC.”
(Source: newswise.com)
New research findings on the brain’s guardian cells
Researcher Johan Jakobsson and his colleagues have now published their results in Nature Communications.
At present, researchers know very little about exactly how microglia work. At the same time, there is a lot of curiosity and high hopes among brain researchers that greater understanding of microglia could lead to entirely new drug development strategies for various brain diseases”, says Johan Jakobsson, research group leader at the Division of Molecular Neurogenetics at Lund University.
What the researchers have now succeeded in identifying is a deviation in the structure of the microglia cells, which makes it possible to visualise them and study their behaviour. By inserting a luminescent protein controlled by a microscopic molecule, microRNA-9, the researchers can now distinguish the microglia and monitor their function over time in the brains of rats and mice.
It has long been known that microglia form the first line of defence of the immune system in diseases of the brain. They move quickly to the affected area and release an arsenal of molecules that protect the nerve cells and clear away damaged tissue.
New research also suggests that microglia not only guard the nerve cells but also play an important role in their basic function.
“This represents a real step forward in technological development. Now we can view microglia in a way that has not been possible before. We and our colleagues now hope to be able to use this technique to study the role of the cells in different disease models, for example Parkinson’s disease and stroke, in which microglia are believed to play an important role”, explains Johan Jakobsson.
Research sheds new light on traumatic brain injuries
Even a mild injury to the brain can have long lasting consequences, including increased risk of cognitive impairment later in life. While it is not yet known how brain injury increases risk for dementia, there are indications that chronic, long-lasting, inflammation in the brain may be important. A new paper by researchers at the University of Kentucky Sanders-Brown Center on Aging (SBCoA), appearing in the Journal of Neuroscience, offers the latest information concerning a “switch” that turns “on” and “off” inflammation in the brain after trauma.
A team of researchers led by Linda Van Eldik, director of SBCoA, used a mouse model to study the role of p38a MAPK in trauma-induced injury responses in the microglia resident immune cell of the brain.
"The p38α MAPK protein is an important switch that drives abnormal inflammatory responses in peripheral tissue inflammatory disorders, including chronic debilitating diseases like rheumatoid arthritis," said Van Eldik.
"However, less is known about the potential importance of p38α MAPK in controlling inflammatory responses in the brain. Our work supports p38α MAPK as a promising clinical target for the treatment of CNS disorders associated with uncontrolled brain inflammation, including trauma, and potentially others like Alzheimer’s disease. We are excited by our findings, and are actively working to develop drugs targeting p38a MAPK designed specifically for diseases of the brain."
Lead author of the paper Adam D. Bachstetter said, “I was surprised when I looked under the microscope at the brain tissue of mice that had a diffuse brain injury. Microglia normally look like a small spider, but after suffering a brain injury the microglia become like angry spiders from a horror movie. In brain-injured mice that lack p38a MAPK there were no angry-looking microglia, only the normal small spider-like cells. When I started the study I never expected the results to be so clear and striking. I believe that the p38a MAPK is a promising clinical target for the treatment of CNS disorders with dysregulated inflammatory responses, but we are still a long way from development of CNS-active p38 inhibitor drugs. “
(Source: eurekalert.org)
New Findings on the Brain’s Immune Cells during Alzheimer’s Disease Progression
The plaque deposits in the brain of Alzheimer’s patients are surrounded by the brain’s own immune cells, the microglia. This was already recognized by Alois Alzheimer more than one hundred years ago. But until today it still remains unclear what role microglia play in Alzheimer’s disease. Do they help to break down the plaque deposit? A study by researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Charité – Universitätsmedizin Berlin has now shed light on these mysterious microglia during the progression of Alzheimer’s disease.
Dr. Grietje Krabbe of the laboratory of Professor Helmut Kettenmann (MDC) and Dr. Annett Halle of the Neuropathology Department of the Charité headed by Professor Frank Heppner demonstrated that the microglial cells around the deposits do not show the classical activation pattern in mouse models of Alzheimer´s disease. On the contrary, in the course of the Alzheimer’s disease they lose two of their biological functions. Both their ability to remove cell fragments or harmful structures and their directed process motility towards acute lesions are impaired. The impact of the latter loss-of-function needs further investigation. The plaques consist of protein fragments, the beta-amyloid peptides, which in Alzheimer’s disease are deposited in the brain over the course of years. They are believed to be involved in destroying the nerve cells of the affected patients, resulting in an incurable cognitive decline.
However, just why the microglial cells, which cluster around the deposits, are inactivated or lose their functionality is still not fully understood. The researchers concluded that this process occurs at a very early stage of disease development and is likely triggered by the beta-amyloid. This is confirmed by the fact that the loss-of-function of the microglial cells in the mice could be reversed by beta-amyloid antibodies thereby decreasing the beta-amyloid burden. According to the researchers, the potential to restore microglial function by directed manipulation should be pursued and exploited to develop treatments for Alzheimer’s disease.
Microglia controls neuron production as brain develops
In a surprise breakthrough, researchers at the UC Davis MIND Institute and their colleagues have found that microglia remove healthy neural progenitor cells (NPCs) through phagocytosis to control neuron production during brain development. This newly discovered mechanism keeps neuron numbers in check, preventing brain overgrowth.
The discovery could open up new avenues for brain research and lead to therapies for a variety of neurological conditions.
The study was published online in the The Journal of Neuroscience.
Microglia are the immune component cell of the central nervous system. Similar to macrophages, microglia provide the brain’s primary defense against pathogens and foreign bodies, clear away dying cells and help repair neural damage. When inactive, they act as sentinels. When a problem is located, they activate and eliminate it. However, until recently, no one had realized the important roles they play in brain development.
"We have known for some time that neurons can undergo apoptosis, a form of cell death, and ultimately be removed by microglia," said Stephen Noctor, assistant professor in the Department of Psychiatry and Behavioral Sciences and the study’s lead author. "But this is new. Microglia are actually eating healthy progenitor cells, thereby regulating the number of neurons produced in the developing brain."
During development, NPCs produce neurons in the brain’s proliferative zones. However, creating too many or too few neurons can have dire consequences.
"If you have too many cells, there’s only so much trophic support (brain infrastructure for cell growth and survival) to keep neurons alive," Noctor said. "All these cells competing for resources could easily throw off connectional properties, altering the way surviving neurons interact. Likewise, having too few cortical cells would have profoundly negative consequences."
(Image: Antoine Triller, Alain Bessis & Serge Marty - Département de Biologie, ENS)
Cajal’s histological preparations and drawings showing some contributions to glial cells. (A) Fibrous astrocyte in the white matter of adult brain (formalin-uranium nitrate and gold-sublimated chloride); (B) Protoplasmic astrocyte in an adult brain (silver carbonate (del Rio) and formalin-uranium nitrate); (C) Twin astrocytes in the human hippocampus (formalin-uranium nitrate); (D) Fibrous astrocytes from the white substance of adult brain (Golgi methods); (E) Olygodendrocytes (ammoniacal silver oxide and Nissl); (F) Microglia cells (ammoniacal silver oxide, reduced silver nitrate and silver carbonate (del Rio) methods).