Posts tagged oligodendrocytes

Alzheimer’s disease has proven to be a difficult enemy to defeat. After all, aging is the No. 1 risk factor for the disorder, and there’s no stopping that.

Most researchers believe the disease is caused by one of two proteins, one called tau, the other beta-amyloid. As we age, most scientists say, these proteins either disrupt signaling between neurons or simply kill them.

Now, a new UCLA study suggests a third possible cause: iron accumulation.

Dr. George Bartzokis, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and senior author of the study, and his colleagues looked at two areas of the brain in patients with Alzheimer’s. They compared the hippocampus, which is known to be damaged early in the disease, and the thalamus, an area that is generally not affected until the late stages. Using sophisticated brain-imaging techniques, they found that iron is increased in the hippocampus and is associated with tissue damage in that area. But increased iron was not found in the thalamus.

The research appears in the August edition of the Journal of Alzheimer’s Disease.

While most Alzheimer’s researchers focus on the buildup of tau or beta-amyloid that results in the signature plaques associated with the disease, Bartzokis has long argued that the breakdown begins much further “upstream.” The destruction of myelin, the fatty tissue that coats nerve fibers in the brain, he says, disrupts communication between neurons and promotes the buildup of the plaques. These amyloid plaques in turn destroy more and more myelin, disrupting brain signaling and leading to cell death and the classic clinical signs of Alzheimer’s.

Myelin is produced by cells called oligodendrocytes. These cells, along with myelin, have the highest levels of iron of any cells in the brain, Bartzokis says, and circumstantial evidence has long supported the possibility that brain iron levels might be a risk factor for age-related diseases like Alzheimer’s. Although iron is essential for cell function, too much of it can promote oxidative damage, to which the brain is especially vulnerable.

In the current study, Bartzokis and his colleagues tested their hypothesis that elevated tissue iron caused the tissue breakdown associated with Alzheimer’s disease. They targeted the vulnerable hippocampus, a key area of the brain involved in the formation of memories, and compared it to the thalamus, which is relatively spared by Alzheimer’s until the very late stages of disease.

The researchers used an MRI technique that can measure the amount of brain iron in ferritin, a protein that stores iron, in 31 patients with Alzheimer’s and 68 healthy control subjects.

In the presence of diseases like Alzheimer’s, as the structure of cells breaks down, the amount of water increases in the brain, which can mask the detection of iron, according to Bartzokis.

"It is difficult to measure iron in tissue when the tissue is already damaged," he said. "But the MRI technology we used in this study allowed us to determine that the increase in iron is occurring together with the tissue damage. We found that the amount of iron is increased in the hippocampus and is associated with tissue damage in patients with Alzheimer’s but not in the healthy older individuals — or in the thalamus. So the results suggest that iron accumulation may indeed contribute to the cause of Alzheimer’s disease."

But it’s not all bad news from this study, Bartzokis noted.

"The accumulation of iron in the brain may be influenced by modifying environmental factors, such as how much red meat and iron dietary supplements we consume and, in women, having hysterectomies before menopause," he said.

In addition, he noted, medications that chelate and remove iron from tissue are being developed by several pharmaceutical companies as treatments for the disorder. This MRI technology may allow doctors to determine who is most in need of such treatments.

(Source: newsroom.ucla.edu)

Myelin, the fatty coating that protects neurons in the brain and spinal cord, is destroyed in diseases such as multiple sclerosis. Researchers have been striving to determine whether oligodendrocytes, the cells that produce myelin, can be stimulated to make new myelin. Using live imaging in zebrafish to track oligodendrocytes in real time, researchers reporting in the June 24 issue of the Cell Press journal Developmental Cell discovered that individual oligodendrocytes coat neurons with myelin for only five hours after they are born. If the findings hold true in humans, they could lead to new treatment strategies for multiple sclerosis.

"The study could help improve our understanding of the triggers needed to encourage cells to produce myelin," says senior author Dr. David Lyons, of the University of Edinburgh, UK. For example, if scientists could determine what is blocking the cells from making myelin after five hours, they might be able to remove that blockage. Alternatively, treatments could focus on creating more new oligodendrocytes rather than trying to stimulate existing oligodendrocytes.

Dr. Lyons and his team used zebrafish to study the formation of myelin sheaths by oligodendrocytes because this laboratory animal is transparent at early stages of its development, which allows investigators to directly observe cells within the organism. It is also known that zebrafish and humans have very similar genes, and these similarities extend to more than 80% of the genes associated with human disease. Zebrafish therefore respond in very similar ways to most drugs used for therapeutic purposes in humans.

"In the future, zebrafish will be used to identify new genes and drugs that can influence myelin formation and myelin repair," says Dr. Lyons.

(Source: eurekalert.org)

Scientists at CWRU School of Medicine Discover New Technique that Holds Promise for the Treatment of Multiple Sclerosis and Cerebral Palsy

Researchers at Case Western Reserve School of Medicine have discovered a technique that directly converts skin cells to the type of brain cells destroyed in patients with multiple sclerosis, cerebral palsy and other so-called myelin disorders.

This discovery appears today in the journal Nature Biotechnology.

This breakthrough now enables “on demand” production of myelinating cells, which provide a vital sheath of insulation that protects neurons and enables the delivery of brain impulses to the rest of the body. In patients with multiple sclerosis (MS), cerebral palsy (CP), and rare genetic disorders called leukodystrophies, myelinating cells are destroyed and cannot be replaced.

The new technique involves directly converting fibroblasts - an abundant structural cell present in the skin and most organs - into oligodendrocytes, the type of cell responsible for myelinating the neurons of the brain.

“Its ‘cellular alchemy,’” explained Paul Tesar, PhD, assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine and senior author of the study. “We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy.”

In a process termed “cellular reprogramming,” researchers manipulated the levels of three naturally occurring proteins to induce fibroblast cells to become precursors to oligodendrocytes (called oligodendrocyte progenitor cells, or OPCs).

Tesar’s team, led by Case Western Reserve researchers and co-first authors Fadi Najm and Angela Lager, rapidly generated billions of these induced OPCs (called iOPCs). Even more important, they showed that iOPCs could regenerate new myelin coatings around nerves after being transplanted to mice—a result that offers hope the technique might be used to treat human myelin disorders.

When oligodendrocytes are damaged or become dysfunctional in myelinating diseases, the insulating myelin coating that normally coats nerves is lost. A cure requires the myelin coating to be regenerated by replacement oligodendrocytes.

Until now, OPCs and oligodendrocytes could only be obtained from fetal tissue or pluripotent stem cells. These techniques have been valuable, but with limitations.
“The myelin repair field has been hampered by an inability to rapidly generate safe and effective sources of functional oligodendrocytes,” explained co-author and myelin expert Robert Miller, PhD, professor of neurosciences at the Case Western Reserve School of Medicine and the university’s vice president for research. “The new technique may overcome all of these issues by providing a rapid and streamlined way to directly generate functional myelin producing cells.”

This initial study used mouse cells. The critical next step is to demonstrate feasibility and safety using human cells in a lab setting. If successful, the technique could have widespread therapeutic application to human myelin disorders.
“The progression of stem cell biology is providing opportunities for clinical translation that a decade ago would not have been possible,” said Stanton Gerson, MD, professor of Medicine-Hematology/Oncology at the School of Medicine and director of the National Center for Regenerative Medicine and the UH Case Medical Center Seidman Cancer Center. “It is a real breakthrough.”

(Source: newswise.com)

Johns Hopkins scientists say they have evidence from animal studies that a type of central nervous system cell other than motor neurons plays a fundamental role in the development of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease. The discovery holds promise, they say, for identifying new targets for interrupting the disease’s progress.

In a study described online in Nature Neuroscience, the researchers found that, in mice bred with a gene mutation that causes human ALS, dramatic changes occurred in oligodendrocytes — cells that create insulation for the nerves of the central nervous system — long before the first physical symptoms of the disease appeared. Oligodendrocytes located near motor neurons — cells that govern movement — died off at very high rates, and new ones regenerated in their place were inferior and unhealthy.

The researchers also found, to their surprise, that suppressing an ALS-causing gene in oligodendrocytes of mice bred with the disease — while still allowing the gene to remain in the motor neurons — profoundly delayed the onset of ALS. It also prolonged survival of these mice by more than three months, a long time in the life span of a mouse. These observations suggest that oligodendrocytes play a very significant role in the early stage of the disease.

“The abnormalities in oligodendrocytes appear to be having a negative impact on the survival of motor neurons,” says Dwight E. Bergles, Ph.D., a co-author and a professor of neuroscience at the Johns Hopkins University School of Medicine. “The motor neurons seem to be dependent on healthy oligodendrocytes for survival, something we didn’t appreciate before.”

“These findings teach us that cells we never thought had a role in ALS not only are involved but also clearly contribute to the onset of the disease,” says co-author Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology at Johns Hopkins and director of the Johns Hopkins Medicine Brain Science Institute.

Scientists have long believed that oligodendrocytes functioned only as structural elements of the central nervous system. They wrap around nerves, making up the myelin sheath that provides the “insulation” that allows nerve signals to be transmitted rapidly and efficiently. However, Rothstein and others recently discovered that oligodendrocytes also deliver essential nutrients to neurons, and that most neurons need this support to survive.

The Johns Hopkins team of Bergles and Rothstein published a paper in 2010 that described in mice with ALS an unexpected massive proliferation of oligodendrocyte progenitor cells in the spinal cord’s motor neurons, and that these progenitors were being mobilized to make new oligodendrocytes. The researchers believed that these cells were multiplying because of an injury to oligodendrocytes, but they weren’t sure what was happening. Using a genetic method of tracking the fate of oligodendrocytes, in the new study, the researchers found that cells present in young mice with ALS were dying off at an increasing rate in concert with advancing disease. Moreover, the development of the newly formed oligodendrocytes was stalled and they were not able to provide motor neurons with a needed source of cell nutrients.

To determine whether the changes to the oligodendrocytes were just a side effect of the death of motor neurons, the scientists used a poison to kill motor neurons in the ALS mice and found no response from the progenitors, suggesting, says Rothstein, that it is the mutant ALS gene that is damaging oligodendrocytes directly.

Meanwhile, in separate experiments, the researchers found similar changes in samples of tissues from the brains of 35 people who died of ALS. Rothstein says it may be possible to see those changes early on in the disease and use MRI technology to follow progression.

“If our research is confirmed, perhaps we can start looking at ALS patients in a different way, looking for damage to oligodendrocytes as a marker for disease progression,” Rothstein says. “This could not only lead to new treatment targets but also help us to monitor whether the treatments we offer are actually working.”

ALS, also known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, affects nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary.

There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival.

Even though myelin loss has not previously been thought to occur in the gray matter, a region in the brain where neurons process information, the researchers in the new study found in ALS patients a significant loss of myelin in one of every three samples of human tissue taken from the brain’s gray matter, suggesting that the oligodendrocytes were abnormal. It isn’t clear if the oligodendrocytes that form this myelin in the gray matter play a different role than in white matter — the region in the brain where signals are relayed.

The findings further suggest that clues to the treatment of other diseases long believed to be focused in the brain’s gray matter — such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease — may be informed by studies of diseases of the white matter, such as multiple sclerosis (MS). Bergles says ALS and MS researchers never really thought their diseases had much in common before.

Oligodendrocytes have been under intense scrutiny in MS, Bergles says. In MS, the disease over time can transform from a remitting-relapsing form — in which myelin is attacked but then is regenerated when existing progenitors create new oligodendrocytes to re-form myelin — to a more chronic stage in which oligodendrocytes are no longer regenerated. MS researchers are working to identify new ways to induce the creation of new oligodendrocytes and improve their survival. “It’s possible that we may be able to dovetail with some of the same therapeutics to slow the progression of ALS,” Bergles says.

(Source: newswise.com)

A study out today in the journal Cell Stem Cell shows that human brain cells created by reprogramming skin cells are highly effective in treating myelin disorders, a family of diseases that includes multiple sclerosis and rare childhood disorders called pediatric leukodystrophies.

The study is the first successful attempt to employ human induced pluripotent stem cells (hiPSC) to produce a population of cells that are critical to neural signaling in the brain. In this instance, the researchers utilized cells crafted from human skin and transplanted them into animal models of myelin disease.

"This study strongly supports the utility of hiPSCs as a feasible and effective source of cells to treat myelin disorders," said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., lead author of the study. "In fact, it appears that cells derived from this source are at least as effective as those created using embryonic or tissue-specific stem cells."

The discovery opens the door to potential new treatments using hiPSC-derived cells for a range of neurological diseases characterized by the loss of a specific cell population in the central nervous system called myelin. Like the insulation found on electrical wires, myelin is a fatty tissue that ensheathes the connections between nerve cells and ensures the crisp transmission of signals from one cell to another. When myelin tissue is damaged, communication between cells can be disrupted or even lost.

The most common myelin disorder is multiple sclerosis, a condition in which the body’s own immune system attacks and destroys myelin. The loss of myelin is also the hallmark of a family of serious and often fatal diseases known as pediatric leukodystrophies. While individually very rare, collectively several thousand children are born in the U.S. with some form of leukodystrophy every year.

The source of the myelin cells in the brain and spinal cord is cell type called the oligodendrocyte. Oligodendrocytes are, in turn, the offspring of another cell called the oligodendrocyte progenitor cell, or OPC. Myelin disorders have long been considered a potential target for cell-based therapies. Scientists have theorized that if healthy OPCs could be successfully transplanted into the diseased or injured brain, then these cells might be able to produce new oligodendrocytes capable of restoring lost myelin, thereby reversing the damage caused by these diseases.

However, several obstacles have thwarted scientists. One of the key challenges is that OPCs are a mature cell in the central nervous system and appear late in development.

"Compared to neurons, which are among the first cells formed in human development, there are more stages and many more steps required to create glial cells such as OPCs," said Goldman. "This process requires that we understand the basic biology and the normal development of these cells and then reproduce this precise sequence in the lab."

Another challenge has been identifying the ideal source of these cells. Much of the research in the field has focused on cells derived from tissue-specific and embryonic stem cells. While research using these cells has yielded critical insight into the biology of stem cells, these sources are not considered ideal to meet demand once stem cell-based therapies become more common.

The discovery in 2007 that human skin cells could be “reprogrammed” to the point where they returned to a biological state equivalent of an embryonic stem cell, called induced pluripotent stem cells, represented a new path forward for scientists. Because these cells – created by using the recipient’s own skin – would be a genetic match, the likelihood of rejection upon transplantation is significantly diminished. These cells also promised an abundant source of material from which to fashion the cells necessary for therapies.

Goldman’s team was the first to successfully master the complex process of using hiPSCs to create OPCs. This process proved time consuming. It took Goldman’s lab four years to establish the exact chemical signaling required to reprogram, produce, and ultimately purify OPCs in sufficient quantities for transplantation and each preparation required almost six months to go from skin cell to a transplantable population of myelin-producing cells.

Once they succeeded in identifying and purifying OPCs from hiPSCs, they then assessed the ability of the cells to make new myelin when transplanted into mice with a hereditary leukodystrophy that rendered them genetically incapable of producing myelin.

They found that the OPCs spread throughout the brain and began to produce myelin. They observed that hiPSC-derived cells did this even more quickly, efficiently, and effectively than cells created using tissue-derived OPCs. The animals were also free of any tumors, a dangerous potential side effect of some stem cell therapies, and survived significantly longer than untreated mice.

"The new population of OPCs and oligodendrocytes was dense, abundant, and complete," said Goldman. "In fact, the re-myelination process appeared more rapid and efficient than with other cell sources."

The next stage in evaluating these cells – clinical studies – may not be long in the offing. Goldman, along with a team of researchers and clinicians from Rochester, Syracuse, and Buffalo, are preparing to launch a clinical trial using OPCs to treat multiple sclerosis. This group, titled the Upstate MS Consortium, has been approved for funding by New York State Stem Cell Science (NYSTEM). While the consortia’s initial study – the early stages of which are scheduled to begin in 2015 – will focus cells derived from tissue sources, Goldman anticipates that hiPSC-derived OPCs will eventually be included in this project.

(Source: eurekalert.org)

Scientists at the Mainz University Medical Center have discovered another molecule that plays an important role in regulating myelin formation in the central nervous system. Myelin promotes the conduction of nerve cell impulses by forming a sheath around their projections, the so-called axons, at specific locations – acting like the plastic insulation around a power cord. The research team, led by Dr. Robin White of the Institute of Physiology and Pathophysiology at the University Medical Center of Johannes Gutenberg University Mainz, recently published their findings in the prestigious journal EMBO reports.

Complex organisms have evolved a technique known as saltatory conduction of impulses to enable nerve cells to transmit information over large distances more efficiently. This is possible because the specialized nerve cell axonal projections involved in conducting impulses are coated at specific intervals with myelin, which acts as an insulating layer. In the central nervous system, myelin develops when oligodendrocytes, which are a type of brain cell, repeatedly wrap their cellular processes around the axons of nerve cells forming a compact stack of cell membranes, a so-called myelin sheath. A myelin sheath not only has a high lipid content but also contains two main proteins, the synthesis of which needs to be carefully regulated.

The current study analyzed the synthesis of myelin basic protein (MBP), a substance which is essential for the formation and stabilization of myelin membranes. In common with all proteins, MBP is generated in a two-stage process originating from basic genetic material in the form of DNA. First, DNA is converted to mRNA, which, in turn, serves as a template for the actual synthesis of MBP. During myelin formation, the synthesis of MBP in oligodendrocytes is suppressed until distinct signals from nerve cells initiate myelination at specific “production sites”. To date, the mechanisms involved in the suppression of MBP synthesis over relatively long periods of time have not been understood. This is where the current work of the Mainz scientists comes in, as they were able to identify a molecule that is responsible for the suppression of MBP synthesis.

"This molecule, called sncRNA715, binds to MBP mRNA, thus preventing MBP synthesis," explains Dr. Robin White. "Our research findings show that levels of sncRNA715 and MBP inversely correlate during myelin formation and that it is possible to influence the extent of MBP production in oligodendrocytes by artificially modifying levels of sncRNA715. This indicates that the recently discovered molecule is a significant factor in the regulation of MBP synthesis."

Understanding the molecular basis for myelin formation is essential with regard to various neurological illnesses that involve a loss of the protective myelin layer. For example, it is still unclear why oligodendrocytes lose their ability to repair the damage to myelin in the progress of multiple sclerosis (MS). “Interestingly, in collaboration with our Dutch colleagues, we have been able to identify a correlation between levels of sncRNA715 and MBP in the brain tissue of MS patients,” Robin White continues. “In contrast with unaffected areas of the brain in which the myelin structure appears normal, there are higher levels of sncRNA715 in affected areas in which myelin formation is impaired. Our findings may help to provide a molecular explanation for myelination failures in illnesses such as multiple sclerosis.”

(Source: uni-mainz.de)

Research may prompt new investigations into white matter’s role in psychiatric disorders as well as connections between mood and myelin diseases, like MS

Animals that are socially isolated for prolonged periods make less myelin in the region of the brain responsible for complex emotional and cognitive behavior, researchers at the University at Buffalo and Mt. Sinai School of Medicine report in Nature Neuroscience online.

The research sheds new light on brain plasticity, the brain’s ability to adapt to environmental changes. It reveals that neurons aren’t the only brain structures that undergo changes in response to an individual’s environment and experience, according to one of the paper’s lead authors, Karen Dietz, PhD, research scientist in the Department of Pharmacology and Toxicology in the UB School of Medicine and Biomedical Sciences.

Dietz did the work while a postdoctoral researcher at Mt. Sinai School of Medicine; Jia Liu, PhD, a Mt. Sinai postdoctoral researcher, is the other lead author.

The paper notes that changes in the brain’s white matter, or myelin, have been seen before in psychiatric disorders, and demyelinating disorders have also had an association with depression. Recently, myelin changes were also seen in very young animals or adolescents responding to environmental changes.

"This research reveals for the first time a role for myelin in adult psychiatric disorders," Dietz says. "It demonstrates that plasticity in the brain is not restricted to neurons, but actively occurs in glial cells, such as the oligodendrocytes, which produce myelin."

(Source: eurekalert.org)

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