Posts tagged microglia
Articles and news from the latest research reports.
Scientists find a new mechanism underlying depression
The World health Organization calls depression “the leading cause of disability worldwide,” causing more years of disability than cancer, HIV/AIDS, and cardiovascular and respiratory diseases combined. In any given year, 5-7% of the world’s population experiences a major depressive episode, and one in six people will at some point suffer from the disease.
Despite recent progress in understanding depression, scientists still don’t understand the biological mechanisms behind it well enough to deliver effective prevention and therapy. One possible reason is that almost all research focuses on the brain’s neurons, while the involvement of other brain cells has not been thoroughly examined.
Now researchers at the Hebrew University of Jerusalem have shown that changes in one type of non-neuronal brain cells, called microglia, underlie the depressive symptoms brought on by exposure to chronic stress. In experiments with animals, the researchers were able to demonstrate that compounds that alter the functioning of microglia can serve as novel and efficient antidepressant drugs.
The findings were published in Molecular Psychiatry, the premier scientific journal in psychiatry and one of the leading journals in medicine and the neurosciences.
The research was conducted by Prof. Raz Yirmiya, director of the Hebrew University’s Psychoneuroimmunology Laboratory, and his doctoral student Tirzah Kreisel, together with researchers at Prof. Yirmiya’s laboratory and at the University of Colorado in Boulder, USA.
The researchers examined the involvement of microglia brain cells in the development of depression following chronic exposure to stress. Comprising roughly 10% of brain cells, microglia are the representatives of the immune system in the brain; but recent studies have shown that these cells are also involved in physiological processes not directly related to infection and injury, including the response to stress.
The researchers mimicked chronic unpredictable stress in humans — a leading causes of depression — by exposing mice to repeated, unpredictable stressful conditions over a period of 5 weeks. The mice developed behavioral and neurological symptoms mirroring those seen in depressed humans, including a reduction in pleasurable activity and in social interaction, as well as reduced generation of new brain cells (neurogenesis) — an important biological marker of depression.
The researchers found that during the first week of stress exposure, microglia cells undergo a phase of proliferation and activation, reflected by increased size and production of specific inflammatory molecules, after which some microglia begin to die. Following the 5 weeks of stress exposure, this phenomenon led to a reduction in the number of microglia, and to a degenerated appearance of some microglia cells, particularly in a specific region of the brain involved in responding to stress.
When the researchers blocked the initial stress-induced activation of microglia with drugs or genetic manipulation, they were able to stop the subsequent microglia cell death and decline, as well as the depressive symptoms and suppressed neurogenesis. However, these treatments were not effective in “depressed” mice, which were already exposed to the 5-weeks stress period and therefore had lower number of microglia. Based on these findings, the investigators treated the “depressed” mice with drugs that stimulated the microglia and increased their number to a normal level.
Prof. Yirmiya said, “We were able to demonstrate that such microglia-stimulating drugs served as effective and fast-acting antidepressants, producing complete recovery of the depressive-like behavioral symptoms, as well as increasing the neurogenesis to normal levels within a few days of treatment. In addition to the clinical importance of these results, our findings provide the first direct evidence that in addition to neurons, disturbances in the functioning of brain microglia cells have a role in causing psychopathology in general, and depression in particular. This suggests new avenues for drug research, in which microglia stimulators could serve as fast-acting antidepressants in some forms of depressive and stress-related conditions.”
The Hebrew University’s technology transfer company, Yissum, has applied for a patent for the treatment of some forms of depression by several specific microglia-stimulating drugs.
Anti-epilepsy drugs can cause inflammations
Glial cells play a crucial role in the nervous system
Hannes Dambach from the Department for Neuroanatomy and Molecular Brain Research, together with a team of colleagues, studied how anti-epilepsy drugs affect the survival of glial cells in cultures. Glial cells are the largest cell group in the brain; they are crucial for supplying neurons with nutrients and affect immune and inflammatory responses. The question of how glial cells are affected by anti-epilepsy drugs had previously not been studied in depth. The RUB work group Clinical Neuroanatomy, headed by Prof Dr Pedro Faustmann, analysed four substances: valproic acid, gabapentin, phenytoin and carbamazepine.
Four anti-epilepsy drugs affect glial cells in different ways
Glial cells treated by the researchers with valproic adic and gabapentin had better survival chances than those treated with phenytoin and carbamazepine. However, carbamazepine had a positive effect, too: it reduced inflammatory responses. Valproic acid, on the other hand, turned out to be pro-inflammatory. In how far the anti-epilepsy drugs affected inflammations was also determined by the applied dose. Consequently, different drugs affected glial cells – and hence indirectly the neurons – in different ways.
Inflammatory responses should be taken under consideration in clinical studies
“Clinical studies should focus not only on the question in how far anti-epilepsy drugs affect the severity and frequency of epileptic seizures,” says Pedro Faustmann. “It is also necessary to test them with regard to the role they play in inflammatory responses in the central nervous system.” Thus, doctors could take the underlying inflammatory condition under consideration when selecting the right anti-epilepsy drug.
Epilepsy may have different causes
In Germany, between 0.5 and 1 percent of the population suffer from epilepsy that requires drug treatment. The disease may have many causes: genetic predisposition, disorders of the central nervous system after meningitis, traumatic brain injury and stroke. Inflammatory responses may also be caused by damage to the brain.
Concussion secrets unveiled in mice and people
There is more than meets the eye following even a mild traumatic brain injury. While the brain may appear to be intact, new findings reported in Nature suggest that the brain’s protective coverings may feel the brunt of the impact.
Using a newly developed mouse trauma model, senior author Dorian McGavern, Ph.D., scientist at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, watched specific cells mount an immune response to the injury and try to prevent more widespread damage. Notably, additional findings suggest a similar immune response may occur in patients with mild head injury.
In this study, researchers also discovered that certain molecules, when applied directly to the mouse skull, can bypass the brain’s protective barriers and enter the brain. The findings suggested that, in the mouse trauma model, one of those molecules may reduce effects of brain injury.
Although concussions are common, not much is known about the effects of this type of damage. As part of this study, Lawrence Latour, Ph.D., a scientist from NINDS and the Center for Neuroscience and Regenerative Medicine, examined individuals who had recently suffered a concussion but whose initial scans did not reveal any physical damage to brain tissue. After administering a commonly used dye during MRI scans, Latour and his colleagues saw it leaking into the meninges, the outer covers of the brain, in 49 percent of 142 patients with concussion.
To determine what happens following this mild type of injury, researchers in Dr. McGavern’s lab developed a new model of brain trauma in mice.
"In our mice, there was leakage from blood vessels right underneath the skull bone at the site of injury, similar to the type of effect we saw in almost half of our patients who had mild traumatic brain injury. We are using this mouse model to look at meningeal trauma and how that spreads more deeply into the brain over time," said Dr. McGavern.
Dr. McGavern and his colleagues also discovered that the intact skull bone was porous enough to allow small molecules to get through to the brain. They showed that smaller molecules reached the brain faster and to a greater extent than larger ones. “It was surprising to discover that all these protective barriers the brain has may not be concrete. You can get something to pass through them,” said Dr. McGavern.
The researchers found that applying glutathione (an antioxidant that is normally found in our cells) directly on the skull surface after brain injury reduced the amount of cell death by 67 percent. When the researchers applied glutathione three hours after injury, cell death was reduced by 51 percent. “This idea that we have a time window within which to work, potentially up to three hours, is exciting and may be clinically important,” said Dr. McGavern.
Glutathione works by decreasing levels of reactive oxygen species (ROS) molecules that damage cells. In this study, high levels of ROS were observed at the trauma site right after the physical brain injury occurred. The massive flood of ROS set up a sequence of events that led to cell death in the brain, but glutathione was able to prevent many of those effects.
In addition, using a powerful microscopic technique, the researchers filmed what was happening just beneath the skull surface within five minutes of injury. They captured never-before-seen details of how the brain responds to traumatic injury and how it mobilizes to defend itself.
Initially, they saw cell death in the meninges and at the glial limitans (a very thin barrier at the surface of the brain that is the last line of defense against dangerous molecules). Cell death in the underlying brain tissue did not occur until 9-12 hours after injury. “You have death in the lining first and then this penetrates into the brain tissue later. The goal of therapies for brain injury is to protect the brain tissue,” said Dr. McGavern.
Almost immediately after head injury, the glial limitans can break down and develop holes, providing a way for potentially harmful molecules to get into the brain. The researchers observed microglia (immune cells that act as first responders in the brain against dangerous substances) quickly moving up to the brain surface, plugging up the holes.
Findings from Dr. McGavern’s lab indicate that microglia do this in two ways. According to Dr. McGavern, “If the astrocytes, the cells that make up the glial limitans, are still there, microglia will come up to ‘caulk’ the barrier and plug up gaps between individual astrocytes. If an astrocyte dies, that results in a larger space in the glial limitans, so the microglia will change shape, expand into a fat jellyfish-like structure and try to plug up that hole. These reactions, which have never been seen before in living brains, help secure the barrier and prevent toxic substances from getting into the brain.”
Studies have suggested that immune responses in the brain can often lead to severe damage. Remarkably, the findings in this study show that the inflammatory response in a mild traumatic brain injury model is actually beneficial during the first 9-12 hours after injury.
Mild traumatic brain injuries are a growing public health concern. According to a report from the Centers of Disease Control and Prevention, in 2009 at least 2.4 million people suffered a traumatic brain injury and 75 percent of those injuries were mild. This study provides insight into the damage that occurs following head trauma and identifies potential therapeutic targets, such as antioxidants, for reducing the damaging effects.
Mysterious brain cells called microglia are starting to reveal their secrets thanks to research conducted at the Weizmann Institute of Science.
Until recently, most of the glory in brain research went to neurons. For more than a century, these electrically excitable cells were believed to perform the entirety of the information processing that makes the brain such an amazing machine. In contrast, cells called glia – which together account for about half of the brain’s volume – were thought to be mere fillers that provided the neurons with support and protection but performed no vital function of their own. In fact, they had been named glia, the Greek for “glue,” precisely because they were considered so unsophisticated.
But in the past few years, the glia cells – particularly the tiny microglia that make up about one-tenth of the brain cells – have been shown to play critical roles both in the healthy and in the diseased brain.
The octopi-like microglia are immune cells that conduct ongoing surveillance, swallowing cellular debris or, in the case of infection, microbes, to protect the brain from injury or disease. But these remarkable cells are more than cleaners: In the past few years, they have been found to be involved in shaping neuronal networks by pruning excessive synapses – the contact points that allow neurons to transmit signals – during embryonic development. They are probably also involved in reshaping the synapses as learning and memory occurs in the adult brain. Defects in microglia are believed to contribute to various neurological diseases, among them Alzheimer’s disease and amyotrophic lateral sclerosis, or ALS. By clarifying how exactly the microglia operate on the molecular level, scientists might be able to develop new therapies for these disorders.
More than a decade ago, Weizmann Institute’s Prof. Steffen Jung developed a transgenic mouse model that for the first time enabled scientists to visualize the highly active microglia in the live brain. Now Jung has made a crucial next step: His laboratory developed a system for investigating the functions of microglia.
The scientists have equipped mice with a genetic switch: an enzyme that can rearrange previously marked portions of the DNA. The switch is activated by a drug: When the mouse receives the drug, the enzyme performs a genetic manipulation – for example, to disable a particular gene. The switch is so designed that over the long term, it targets only the microglia, but not other cells in the brain or in the rest of the organism. In this manner, researchers can clarify not only the function of the microglia, but the roles of different genes in their mechanism of action.
As reported in Nature Neuroscience, Weizmann scientists, in collaboration with the team of Prof. Marco Prinz at the University of Freiburg, Germany, recently used this system to examine the role of an inflammatory gene expressed by the microglia. They found that the microglia contribute to an animal disease equivalent of multiple sclerosis. Prof. Jung’s team included Yochai Wolf, Diana Varol and Dr. Simon Yona, all of Weizmann’s Immunology Department.
Common brain cell plays key role in shaping neural circuit
Stanford University School of Medicine neuroscientists have discovered a new role played by a common but mysterious class of brain cells.
Their findings, published online Nov. 24 in Nature, show that these cells, called astrocytes because of their star-like shape, actively refine nerve-cell circuits by selectively eliminating synapses — contact points through which nerve cells, or neurons, convey impulses to one another — much as a sculptor chisels away excess bits of rock to create an artwork.
“This was an entirely unknown function of astrocytes,” said Ben Barres, MD, PhD, professor and chair of neurobiology and the study’s senior author. The lead author was Won-Suk Chung, PhD, a postdoctoral scholar in Barres’ lab. More than one-third of all the cells in the human brain are astrocytes. But until quite recently, their role in the brain has remained obscure.
The study was performed on brain tissue from mice, but it is likely to apply to people as well, Barres said.
The discovery adds to a growing body of evidence that substantial remodeling of brain circuits takes place in the adult brain and that astrocytes are master sculptors of its constantly evolving synaptic architecture. The findings also raise the question of whether deficits and excesses in this astrocytic function could underlie, respectively, the loss of this remodeling capacity in old age or the wholesale destruction of synapses that erupts in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease.
“Astrocytes are in the driver’s seat when it comes to synapse formation, function and elimination,” Barres said. In previous studies, he and his colleagues have shown that astrocytes play a critical role in determining exactly where and when new synapses are generated.
The new study showed that astrocytes’ synapse-gobbling behavior persists into adulthood and is triggered by activity in the neurons, suggesting astrocytes may be central to the constant fine-tuning and reconfiguring of brain circuits occurring throughout our lives in response to experiences such as learning, recollection, emotion and motion. While a healthy brain’s neurons remain intact for much a person’s lifetime, the connections between them — the synapses — are constantly forming, strengthening, weakening or dying.
The Barres team also has previously implicated another brain cell type, collectively known as microglia, in synaptic pruning in early development, when the young brain undergoes ongoing episodes of circuit remodeling. The role of astrocytes in synaptic refining, the new study shows, differs from that of microglia both in timing and mechanism.
Barres’ team began to suspect astrocytes’ participation in the pruning process when, having developed methods for isolating exceptionally pure populations of different types of brain cells, they saw that the genes for two separate biochemical pathways were active in astrocytes. Both of these pathways are involved in phagocytosis, the trash-collection process by which specialized cells in the body engulf, ingest and digest dead cells; foreign materials, including bacteria; debris from wounds; and so forth. At the leading end of the two pathways were two phagocytic receptors, MERKTK and MEGF10, which in other cell types have been shown to bind to particular proteins on targeted cells or materials, triggering the ensuing engulfment, ingestion and digestion of the targets.
It’s known that much of an astrocyte’s surface membrane is typically in close contact with neurons. In fact, a single astrocyte may ensheathe thousands of synapses. It was only natural, Barres said, to wonder whether astrocytes play some role in eliminating synapses.
The researchers first demonstrated that both MERKTK and MEGF10, along with their entire tool kits of cooperating proteins, are present in living astrocytes in the mouse brain. (In unpublished work, they have since confirmed this using human astrocytes.) Next, they showed that mouse astrocytes in a lab dish eagerly gobbled up synapses and dispatched them to their lysosomes, highly acidic internal garbage disposals found in most cells in the body. But this engulfment was dependent on astrocytes having functional MEGF10 and MERTK. Disabling one or the other receptor’s function cut in half astrocytes’ ability to engorge themselves on synapses; knocking out both receptors lowered the synapse-eating activity by about 90 percent.
To see if this happens in real life, Chung, Barres and their associates turned to a familiar experimental model: a brain area called the lateral geniculate nucleus, which is a critical component of the brain’s vision-processing system. The LGN receives inputs from neurons just a couple of steps downstream from the photoreceptors in the retina. In early development, neurons in the LGN are innervated by inputs from both eyes. But at a critical point in development, a highly selective synaptic-pruning process kicks in, resulting in each neuron from one side of the LGN being contacted pretty much only by neurons from a single eye. This pruning process in the LGN is dependent on the transmission of waves of spontaneous neuronal impulses originating in the retina.
Experimenting with mice that had entered the critical period for synaptic pruning in the LGN, the investigators labeled the incoming neurons in this system with different-colored stains so their synaptic regions could be identified within astrocytes if the astrocytes ate them up. And sure enough, a lot of this label turned up inside astrocytes’ lysosomes, indicating that astrocytes were actively ingesting synapses. Knocking out one or another or, especially, both of the two phagocytic receptors greatly reduced the amount of labeled synaptic material found in astrocytes. Impairing astrocytic MERKTK and MEGF10 function also caused a failure of LGN neurons to restrict their inputs to only neurons from just one eye, clearly implicating astrocytes in that process. Electrophysiology experiments proved that the LGN neurons in the MERKTK- and MEGF10-knockout mice retained an excessive number of synapses, demonstrating that astrocytes play an active role in pruning synapses during development.
Importantly, injection of a drug blocking the transmission of spontaneous waves of electrical impulses originating in the retina severely impaired astrocytes’ ability to eat synapses, showing that the synapse-pruning propensity is linked to neuronal activity. Other tests showed that astrocytic phagocytosis of synapses continues into adulthood.
Barres said this raises the question of whether astrocytes function throughout life to continually restructure our neuronal circuitry in response to experientially induced brain activity. If astrocytes’ synaptic snacking slows with aging, as that of other phagocytic cell types is known to do, it could reduce the aging brain’s capacity to adapt to new experiences, he said. “Maybe you need the astrocytes to gobble up old synapses to make room for new ones.”
If so, it may be possible someday to design drugs to keep astrocytes’ phagocytic process from slowing, Barres added. Such drugs might prevent the accumulation in aging brains of past-their-prime synapses, which are vulnerable to degeneration in Alzheimer’s, Parkinson’s and other neurodegenerative disease characterized by massive synapse loss.
Genes uniquely expressed by the brain’s immune cells
Massachusetts General Hospital (MGH) investigators have used a new sequencing method to identify a group of genes used by the brain’s immune cells – called microglia – to sense pathogenic organisms, toxins or damaged cells that require their response. Identifying these genes should lead to better understanding of the role of microglia both in normal brains and in neurodegenerative disorders and may lead to new ways to protect against the damage caused by conditions like Alzheimer’s and Parkinson’s diseases. The study, which has been published online in Nature Neuroscience, also finds that the activity of microglia appears to become more protective with aging, as opposed to increasingly toxic, which some previous studies had suggested.
"We’ve been able to define, for the first time, a set of genes microglia use to sense their environment, which we are calling the microglial sensome," says Joseph El Khoury, MD, of the MGH Center for Immunology and Inflammatory Diseases and Division of Infectious Diseases, senior author of the study. "Identifying these genes will allow us to specifically target them in diseases of the central nervous system by developing ways to upregulate or downregulate their expression."
A type of macrophage, microglia are known to constantly survey their environment in order to sense the presence of infection, inflammation, and injured or dying cells. Depending on the situation they encounter, microglia may react in a protective manner – engulfing pathogenic organisms, toxins or damaged cells – or release toxic substances that directly destroy microbes or infected brain cells. Since this neurotoxic response can also damage healthy cells, keeping it under control is essential, and excess neurotoxicity is known to contribute to the damage caused by several neurodegenerative disorders.
El Khoury’s team set out to define the transcriptome – the complete set of RNA molecules transcribed by a cell – of the microglia of healthy, adult mice and compared that expression profile to those of macrophages from peripheral tissues of the same animals and of whole brain tissue. Using a technique called direct RNA sequencing, which is more accurate than previous methods, they identified a set of genes uniquely expressed in the microglia and measured their expression levels, the first time such a gene expression ‘snapshot’ has been produced for any mammalian brain cell, the authors note.
Since aging is known to alter gene expression throughout the brain, the researchers then compared the sensome of young adult mice to that of aged mice. They found that – contrary to what previous studies had suggested – the expression of genes involved in potentially neurotoxic actions, such as destroying neurons, was downregulated as animals aged, while the expression of neuroprotective genes involved in sensing and removing pathogens was increased. El Khoury notes that the earlier studies suggesting increased neurotoxicity with aging did not look at the cells’ full expression profile and often were done in cultured cells, not in living animals.
"Establishing the sensome of microglia allows us to clearly understand how they interact with and respond to their environment under normal conditions," he explains. "The next step is to see what happens under pathologic conditions. We know that microglia become more neurotoxic as Alzheimer’s disease and other neurodegenerative disorders progress, and recent studies have identified two of the microglial sensome genes as contributing to Alzheimer’s risk. Our next steps should be defining the sensome of microglia and other brain cells in humans, identifying how the sensome changes in central nervous system disorders, and eventually finding ways to safely manipulate the sensome pharmacologically."
(Source: massgeneral.org)
Learning how the brain takes out its trash may help decode neurological diseases
Imagine that garbage haulers don’t exist. Slowly, the trash accumulates in our offices, our homes, it clogs the streets and damages our cars, causes illness and renders normal life impossible.
Garbage in the brain, in the form of dead cells, must also be removed before it accumulates, because it can cause both rare and common neurological diseases, such as Parkinson’s. Now, University of Michigan researchers are a leap closer to decoding the critical process of how the brain clears dead cells, said Haoxing Xu, associate professor in the U-M Department of Molecular, Cellular and Developmental Biology.
A new U-M study identified two critical components of this cell clearing process: an essential calcium channel protein, TRPML1, that helps the so-called garbage collecting cells, called microphages or microglia, to clear out the dead cells; and alipid molecule, which helps activate TRPML1 and the process that allows the microphages to remove these dead cells.
Moreover, the Xu lab identified a synthetic chemical compound that can activate TRPML1. Because this chemical compound ultimately helps activate this cell-clearing process, it provides a drug target that could help combat these neurological diseases.
"This is clearly a drug target," Xu said. "What this paper picks out is exactly what is going wrong in this process."
Scientists began by looking at a very rare neurodegenerative disease called Type IV Mucolipidosis, a childhood neurodegenerative disease characterized by multiple disabilities.
Xu’s group found that lack of TRPML1 function, which is the channel through which calcium is released from the lysosome—the cell’s recycling center—into the microphage cells, contributes to these neurodegenerative conditions. If this calcium channel doesn’t work, calcium cannot be released, and dead cells aren’t removed, Xu said. The synthetic chemical compound stimulates the TRPML1 calcium channel to release the calcium into the cell.
Further, dead cells “are bad for live cells,” Xu said. An excess of dead cells leads the macrophage cells to also kill healthy neurons necessary for neurological function, which in turn can lead to these neurodegenerative diseases.
There are many neurodegenerative diseases, some very rare and some more common, such as Parkinson’s and ALS. The common thread among them is the dearth of live and functioning neurons, which prevents the neurological system from carrying out normal functions, Xu said.
Thus, identifying a lipid molecule and also chemical compounds that stimulates proper function of the TRMPL1 function could revolutionize the treatment of these neurodegenerative diseases.
The next step in Xu’s research is to test how these general observations are helpful to the neurological diseases and whether the compound is effective in animal models of neurological diseases.
The paper, “A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis,” appeared Aug. 29 online in Developmental Cell.
Study identifies new culprit that may make aging brains susceptible to neurodegenerative diseases
The steady accumulation of a protein in healthy, aging brains may explain seniors’ vulnerability to neurodegenerative disorders, a new study by researchers at the Stanford University School of Medicine reports.
The study’s unexpected findings could fundamentally change the way scientists think about neurodegenerative disease.
The pharmaceutical industry has spent billions of dollars on futile clinical trials directed at treating Alzheimer’s disease by ridding brains of a substance called amyloid plaque. But the new findings have identified another mechanism, involving an entirely different substance, that may lie at the root not only of Alzheimer’s but of many other neurodegenerative disorders — and, perhaps, even the more subtle decline that accompanies normal aging.
The study, published Aug. 14 in the Journal of Neuroscience, reveals that with advancing age, a protein called C1q, well-known as a key initiator of immune response, increasingly lodges at contact points connecting nerve cells in the brain to one another. Elevated C1q concentrations at these contact points, or synapses, may render them prone to catastrophic destruction by brain-dwelling immune cells, triggered when a catalytic event such as brain injury, systemic infection or a series of small strokes unleashes a second set of substances on the synapses.
“No other protein has ever been shown to increase nearly so profoundly with normal brain aging,” said Ben Barres, MD, PhD, professor and chair of neurobiology and senior author of the study. Examinations of mouse and human brain tissue showed as much as a 300-fold age-related buildup of C1q.
The finding was made possible by the diligence and ingenuity of the study’s lead author, Alexander Stephan, PhD, a postdoctoral scholar in Barres’ lab. Stephan screened about 1,000 antibodies before finding one that binds to C1q and nothing else. (Antibodies are proteins, generated by the immune system, that adhere to specific “biochemical shapes,” such as surface features of invading pathogens.)
Comparing brain tissue from mice of varying ages, as well as postmortem samples from a 2-month-old infant and an older person, the researchers showed that these C1q deposits weren’t randomly distributed along nerve cells but, rather, were heavily concentrated at synapses. Analyses of brain slices from mice across a range of ages showed that as the animals age, the deposits spread throughout the brain.
“The first regions of the brain to show a dramatic increase in C1q are places like the hippocampus and substantia nigra, the precise brain regions most vulnerable to neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, respectively,” said Barres. Another region affected early on, the piriform cortex, is associated with the sense of smell, whose loss often heralds the onset of neurodegenerative disease.
Other scientists have observed moderate, age-associated increases (on the order of three- or four-fold) in brain levels of the messenger-RNA molecule responsible for transmitting the genetic instructions for manufacturing C1q to the protein-making machinery in cells. Testing for messenger-RNA levels — typically considered reasonable proxies for how much of a particular protein is being produced — is fast, easy and cheap compared with analyzing proteins.
But in this study, Barres and his colleagues used biochemical measures of the protein itself. “The 300-fold rise in C1q levels we saw in 2-year-old mice — equivalent to 70- or 80-year-old humans — knocked my socks off,” Barres said. “I was not expecting that at all.”
C1q is the first batter on a 20-member team of immune-response-triggering proteins, collectively called the complement system. C1q is capable of clinging to the surface of foreign bodies such as bacteria or to bits of our own dead or dying cells. This initiates a molecular chain reaction known as the complement cascade. One by one, the system’s other proteins glom on, coating the offending cell or piece of debris. This in turn draws the attention of omnivorous immune cells that gobble up the target.
The brain has its own set of immune cells, called microglia, which can secrete C1q. Still other brain cells, called astrocytes, secrete all of C1q’s complement-system “teammates.” The two cell types work analogously to the two tubes of an Epoxy kit, in which one tube contains the resin, the other a catalyst.
Previous work in Barres’ lab has shown that the complement cascade plays a critical role in the developing brain. A young brain generates an excess of synapses, creating a huge range of options for the potential formation of new neural circuits. These synapses strengthen or weaken over time, in response to their heavy use or neglect. The presence of feckless connections contributes noise to the system, so the efficiency of the maturing brain’s architecture is improved if these underused synapses are pruned away.
In a 2007 paper in Cell, Barres’ group reported that the complement system is essential to synaptic pruning in normal, developing brains. Then in 2012, in Neuron, in a collaboration with the lab of Harvard neuroscientist Beth Stevens, PhD, they showed that it is specifically microglia — the brain’s in-house immune cells — that attack and ingest complement-coated synapses.
Barres now believes something similar is happening in the normal, aging brain. C1q, but not the other protein components of the complement system, gradually becomes highly prevalent at synapses. By itself, this C1q buildup doesn’t trigger wholesale synapse loss, the researchers found — although it does seem to impair their performance. Old mice whose capacity to produce C1q had been eliminated performed subtly better on memory and learning tests than normal older mice did.
Still, this leaves the aging brain’s synapses precariously perched on the brink of catastrophe. A subsequent event such as brain trauma, a bad case of pneumonia or perhaps a series of tiny strokes that some older people experience could incite astrocytes — the second tube in the Epoxy kit — to start secreting the other complement-system proteins required for synapse destruction.
Most cells in the body have their own complement-inhibiting agents. This prevents the wholesale loss of healthy tissue during an immune attack on invading pathogens or debris from dead tissue during wound healing. But nerve cells lack their own supply of complement inhibitors. So, when astrocytes get activated, their ensuing release of C1q’s teammates may set off a synapse-destroying rampage that spreads “like a fire burning through the brain,” Barres said.
“Our findings may well explain the long-mysterious vulnerability specifically of the aging brain to neurodegenerative disease,” he said. “Kids don’t get Alzheimer’s or Parkinson’s. Profound activation of the complement cascade, associated with massive synapse loss, is the cardinal feature of Alzheimer’s disease and many other neurodegenerative disorders. People have thought this was because synapse loss triggers inflammation. But our findings here suggest that activation of the complement cascade is driving synapse loss, not the other way around.”
(Source: med.stanford.edu)
Lack of immune cell receptor impairs clearance of amyloid beta protein from the brain
Identification of a protein that appears to play an important role in the immune system’s removal of amyloid beta (A-beta) protein from the brain could lead to a new treatment strategy for Alzheimer’s disease. The report from researchers at Massachusetts General Hospital (MGH) has been published online in Nature Communications.
"We identified a receptor protein that mediates clearance from the brain of soluble A-beta by cells of the innate immune system," says Joseph El Khoury, MD, of the Center for Immunology and Inflammatory Diseases in the MGH Division of Infectious Diseases, co-corresponding author of the report. "We also found that deficiency of this receptor in a mouse model of Alzheimer’s disease leads to greater A-beta deposition and accelerated death, while upregulating its expression enhanced A-beta clearance from the brain."
The brain’s immune system – which includes cells like microglia, monocytes and macrophages that engulf and remove foreign materials – appears to play a dual role in neurodegenerative disorders like Alzheimer’s disease. At early stages, these cells mount a response against the buildup of A-beta, the primary component of the toxic plaques found in the brains of patients with the devastating neurological disorder. But as the disease progresses and A-beta plaques become larger, not only do these cells lose their ability to take up A-beta, they also release inflammatory chemicals that cause further damage to brain tissue.
In their investigation of factors that may underlie the breakdown of the immune system’s clearance of A-beta, El Khoury’s team with the hypothesis that, in addition to recognizing and binding to the insoluble form of A-beta found in amyloid plaques, the brain’s immune cells might also interact with soluble forms of A-beta that could begin accumulating in the brain before plaques appear. The researchers first examined a group of receptor proteins known to be used by microglia, monocytes and macrophages to interact with insoluble A-beta. Although any role for these proteins in Alzheimer’s disease has not been known, the MGH investigators previously found that their expression in a mouse model of the disease dropped as the animals aged.
After they first identified the involvement of a receptor called Scara1 in the uptake of soluble A-beta by monocytes and macrophages, the researchers then confirmed that Scara1 appears to be the major receptor for recognition and clearance of A-beta by the innate immune system, the body’s first line of defense. In a mouse model of Alzheimer’s, animals that were missing one or both copies of the Scara1 gene died several months earlier than did those with two functioning copies. By the age of 8 months, Alzheimer’s mice with no functioning Scara1 genes had double the A-beta in their brains as did a control group of Alzheimer’s mice, while normal mice had virtually none.
To investigate possible therapeutic application of the role of Scara1 in A-beta clearance, the MGH team treated cultured immune cells with Protollin, a compound that has been used to enhance the immune response to certain vaccines. Application of Protollin to immune cells tripled their expression of Scara1 and also increased levels of a protein that attracts other immune cells. Adding Protollin-stimulated microglia to brain samples from Alzheimer’s mice reduced the size and number of A-beta deposits in the hippocampus, an area particularly damaged by the disease, but that reduction was significantly less when microglia from Scara1-deficient mice were used.
El Khoury notes that previous research showed that Protollin treatment reduced A-beta deposits in Alzheimer’s mice and the current study reveals the probable mechanism behind that finding. “Upregulating Scara1 expression is a promising approach to treating Alzheimer’s disease,” he says. “First we need to duplicate these studies using human cells and identify new classes of molecules that can safely increase Scara1 expression or activity. That could potentially lead to ways of harnessing the immune system to delay the progression of this disease.” El Khoury is an associate professor of Medicine at Harvard Medical School.
(Source: massgeneral.org)
Gladstone Scientists Identify Key Biological Mechanism in Multiple Sclerosis
Scientists at the Gladstone Institutes have defined for the first time a key underlying process implicated in multiple sclerosis (MS)—a disease that causes progressive and irreversible damage to nerve cells in the brain and spinal cord. This discovery offers new hope for the millions who suffer from this debilitating disease for which there is no cure.
Researchers in the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, have identified in animal models precisely how a protein that seeps from the blood into the brain sets off a response that, over time, causes the nerve cell damage that is a key indicator of MS. These findings, which are reported in the latest issue of Nature Communications, lay the groundwork for much-needed therapies to treat this disease.
(Source: gladstoneinstitutes.org)