Neuroscience

When the era of regenerative medicine dawned more than three decades ago, the potential to replenish populations of cells destroyed by disease was seen by many as the next medical revolution. However, what followed turned out not to be a sprint to the clinic, but rather a long tedious slog carried out in labs across the globe required to master the complexity of stem cells and then pair their capabilities and attributes with specific diseases.

In a review article appearing today in the journal Science, University of Rochester Medical Center scientists Steve Goldman, M.D., Ph.D., Maiken Nedergaard, Ph.D., and Martha Windrem, Ph.D., contend that researchers are now on the threshold of human application of stem cell therapies for a class of neurological diseases known as myelin disorders – a long list of diseases that include conditions such as multiple sclerosis, white matter stroke, cerebral palsy, certain dementias, and rare but fatal childhood disorders called pediatric leukodystrophies.

"Stem cell biology has progressed in many ways over the last decade, and many potential opportunities for clinical translation have arisen," said Goldman. "In particular, for diseases of the central nervous system, which have proven difficult to treat because of the brain’s great cellular complexity, we postulated that the simplest cell types might provide us the best opportunities for cell therapy."

The common factor in myelin disorders is a cell called the oligodendrocyte. These cells arise, or are created, by another cell found in the central nervous system called the glial progenitor cell. Both oligodendrocytes and their “sister cells” – called astrocytes – share this same parent and serve critical support functions in the central nervous systems.

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Five scientists, including two from Simon Fraser University, have discovered that 30 per cent of our likelihood of developing Multiple Sclerosis (MS) can be explained by 475,806 genetic variants in our genome. Genome-wide Association Studies (GWAS) commonly screen these variants, looking for genetic links to diseases.

Corey Watson, a recent SFU doctoral graduate in biology, his thesis supervisor SFU biologist Felix Breden and three scientists in the United Kingdom have just had their findings published online in Scientific Reports. It’s a sub-publication of the journal Nature.

An inflammatory disease of the central nervous system, MS is the most common neurological disorder among young adults. Canada has one of the highest MS rates in the world.

Watson and his colleagues recently helped quantify MS genetic susceptibility by taking a closer look at GWAS-identified variants in the major histocompatibility complex (MHC) region in 1,854 MS patients. The region has long been associated with MS susceptibility.

The MS patients’ variants were compared to those of 5,164 controls, people without MS.

They noted that eight percent of our 30-per-cent genetic susceptibility to MS is linked to small DNA variations on chromosome 6, which have also long been associated with MS susceptibility.

The MHC encodes proteins that facilitate communication between certain cells in the immune system. Outside of the MHC, a good majority of genetic susceptibility can’t be nailed down because current studies don’t allow for all variants in our genome to be captured.

 “Much of the liability is unaccounted for because current research methods don’t enable us to fully interrogate our genome in the context of risk for MS or other diseases,” says Watson.

The researchers believe that one place to look for additional genetic causes of MS may be in genes that have variants that are rare in the population. “The importance of rare gene variants in MS has been illustrated in two recent studies,” notes Watson, now a postdoctoral researcher at the Mount Sinai School of Medicine in New York.

“But these variants, too, are generally poorly represented by genetic markers captured in GWAS, like the one our study was based on.”

Researchers from UCL have found that lonely people have less grey matter in a part of the brain associated with decoding eye gaze and other social cues.

Published in the journal of Current Biology, the study also suggests that through training people might be able to improve their social perception and become less lonely.

“What we’ve found is the neurobiological basis for loneliness,” said lead author Dr Ryota Kanai (UCL Institute of Cognitive Neuroscience). “Before conducting the research we might have expected to find a link between lonely people and the part of the brain related to emotions and anxiety, but instead we found a link between loneliness and the amount of grey matter in the part of the brain involved in basic social perception.” 

To see how differences in loneliness might be reflected in the structure of the brain regions associated with social processes, the team scanned the brains of 108 healthy adults and gave them a number of different tests. Loneliness was self-reported and measured using a UCLA loneliness scale questionnaire.

When looking at full brain scans they saw that lonely individuals have less greymatter in the left posterior superior temporal sulcus (pSTS)—an area implicated in basic social perception, confirming that loneliness was associated with difficulty in processing social cues.

“The pSTS plays a really important role in social perception, as it’s the initial step of understanding other people,” said Dr Kanai. “Therefore the fact that lonely people have less grey matter in their pSTS is likely to be the reason why they have poorer perception skills.”

In order to gauge social perception, participants were presented with three different faces on a screen and asked to judge which face had misaligned eyes and whether they were looking either right or left. Lonely people found it much harder to identify which way the eyes were looking, confirming the link between loneliness, the size of the pSTS and the perception of eye gaze. 

“From the study we can’t tell if loneliness is something hardwired or environmental,” said co-author Dr Bahador Bahrami (UCL Institute of Cognitive Neuroscience). “But one possibility is that people who are poor at reading social cues may experience difficulty in developing social relationships, leading to social isolation and loneliness.” 

One way to counter this loneliness could be through social perception training with a smartphone app.

“The idea of training is one way to address this issue, as by maybe using a smartphone app to improve people’s basic social perception such as eye gaze, hopefully we can help them to lead less lonely lives,” said Dr Kanai.

Joint research between the University of Michigan and the Argentina-based National Council of Science and Technology (CONICET) has shed light on one of the most frustrating mysteries of weight loss – why the weight inevitably comes back.

A novel animal model showed that the longer mice remained overweight, the more “irreversible” obesity became, according to the new study that appeared online ahead of print Oct.24 in the Journal of Clinical Investigation.

Over time, the static, obese state of the mice reset the “normal,” body weight set point to become permanently elevated, despite dieting that initially worked to shed pounds, authors say.

“Our model demonstrates that obesity is in part a self-perpetuating disorder and the results further emphasize the importance of early intervention in childhood to try to prevent the condition whose effects can last a lifetime,” says senior author Malcolm J. Low, M.D., Ph.D., professor of molecular and integrative physiology and internal medicine.

Study finds moderate consumption decreases number of new brain cells

Drinking a couple of glasses of wine each day has generally been considered a good way to promote cardiovascular and brain health. But a new Rutgers University study indicates that there is a fine line between moderate and binge drinking – a risky behavior that can decrease the making of adult brain cells by as much as 40 percent.

In a study posted online and scheduled to be published in the journal Neuroscience on November 8, lead author Megan Anderson, a graduate student working with Tracey J. Shors, Professor II in Behavioral and Systems Neuroscience in the Department of Psychology, reported that moderate to binge drinking – drinking less during the week and more on the weekends – significantly reduces the structural integrity of the adult brain.

“Moderate drinking can become binge drinking without the person realizing it,” said Anderson.“In the short term there may not be any noticeable motor skills or overall functioning problems, but in the long term this type of behavior could have an adverse effect on learning and memory.”

In an early-stage breakthrough, a team of Northwestern University scientists has developed a new family of compounds that could slow the progression of Parkinson’s disease.

Parkinson’s, the second most common neurodegenerative disease, is caused by the death of dopamine neurons, resulting in tremors, rigidity and difficulty moving. Current treatments target the symptoms but do not slow the progression of the disease.

The new compounds were developed by Richard B. Silverman, the John Evans Professor of Chemistry at the Weinberg College of Arts and Sciences and inventor of the molecule that became the well-known drug Lyrica, and D. James Surmeier, chair of physiology at Northwestern University Feinberg School of Medicine. Their research was published Oct. 23 in the journal Nature Communications.

The compounds work by slamming the door on an unwelcome and destructive guest — calcium. The compounds target and shut a relatively rare membrane protein that allows calcium to flood into dopamine neurons. Surmeier’s previously published research showed that calcium entry through this protein stresses dopamine neurons, potentially leading to premature aging and death. He also identified the precise protein involved — the Cav1.3 channel.

"These are the first compounds to selectively target this channel," Surmeier said. "By shutting down the channel, we should be able to slow the progression of the disease or significantly reduce the risk that anyone would get Parkinson’s disease if they take this drug early enough."

"We’ve developed a molecule that could be an entirely new mechanism for arresting Parkinson’s disease, rather than just treating the symptoms," Silverman said.

The compounds work in a similar way to the drug isradipine, for which a Phase 2 national clinical trial with Parkinson’s patients –- led by Northwestern Medicine neurologist Tanya Simuni, M.D. — was recently completed. But because isradipine interacts with other channels found in the walls of blood vessels, it can’t be used in a high enough concentration to be highly effective for Parkinson’s disease. (Simuni is the Arthur C. Nielsen Professor of Neurology at the Feinberg School and a physician at Northwestern Memorial Hospital.)

The challenge for Silverman was to design new compounds that specifically target this rare Cav1.3 channel, not those that are abundant in blood vessels. He and colleagues first used high-throughput screening to test 60,000 existing compounds, but none did the trick.

"We didn’t want to give up," Silverman said. He then tested some compounds he had developed in his lab for other neurodegenerative diseases. After Silverman identified one that had promise, Soosung Kang, a postdoctoral associate in Silverman’s lab, spent nine months refining the molecules until they were effective at shutting only the Cav1.3 channel.

In Surmeier’s lab, the drug developed by Silverman and Kang was tested by graduate student Gary Cooper in regions of a mouse brain that contained dopamine neurons. The drug did precisely what it was designed to do, without any obvious side effects.

"The drug relieved the stress on the cells," Surmeier said.

For the next step, the Northwestern team has to improve the pharmacology of the compounds to make them suitable for human use, test them on animals and move to a Phase 1 clinical trial.

"We have a long way to go before we are ready to give this drug, or a reasonable facsimile, to humans, but we are very encouraged," Surmeier said.

In an Australian first, researchers are studying Magnetic Seizure Therapy (MST) as an alternative treatment for the 30 per cent of patients suffering from depression who don’t respond to traditional treatment.

The treating team; Anne Maree Clinton, Dr Kate Hoy and Professor Paul Fitzgerald with the MST machine

The study, led by researchers from the Monash Alfred Psychiatry Research Centre (MAPrc) and funded by beyondblue and the National Health and Medical Research Council (NHMRC), has been published in two leading journals: Psychiatry Research: Neuroimaging and Depression and Anxiety. Both papers are a result of the same study.

MAPrc Deputy Director Professor Paul Fitzgerald, who led the study, said depression was a common and disabling disorder, affecting up to one in five Australians during their lifetime.

“Electroconvulsive Therapy (ECT) is one of the only established interventions for treatment resistant depression,” Professor Fitzgerald said.

“But use of ECT is limited due to the presence of memory-related side effects and associated stigma.”

For this reason, the MAPrc researchers began exploring new treatment options. MST is a brain-stimulation technique that may have similar clinical effects to ECT without the unwanted side effects.

“In MST, a seizure is induced through the use of magnetic stimulation rather than a direct electrical current like ECT. Magnetic fields are able to pass freely into the brain, making it possible to more precisely focus stimulation,” Professor Fitzgerald said.

“By avoiding the use of direct electrical currents and inducing a more focal stimulation, it is thought that MST will result in an improvement of depressive symptoms without the memory difficulties seen with ECT.”

Research is still at an early stage and MST is only available in a handful of locations worldwide. The MAPrc is the only centre in Australia conducting trials with this therapy.

The study found that MST resulted in an overall significant reduction in depression symptoms; 40 per cent showed overall improvement and 30 per cent showed some improvement. None of the trial participants complained of cognitive side effects.

“MST shows antidepressant efficacy without apparent cognitive side effects. However, substantial research is required to understand the optimal conditions for stimulation and to compare MST to established treatments, including ECT,” Professor Fitzgerald said.

“In order to accurately assess the comparable efficacy of MST to ECT, large-scale randomised controlled trials are required. There remains considerable work to be done before statements of the relative efficacy of these treatments can be made.”

Professor Fitzgerald and his team have received more funding from beyondblue and the NHMRC to carry out a large-scale trial on MST as an alternative treatment for depression.

TAU researcher discovers that family history of schizophrenia is a risk factor for autism

Autism Spectrum Disorders (ASD), a category that includes autism, Asperger Syndrome, and Pervasive Developmental Disorder, are characterized by difficulty with social interaction and communication, or repetitive behaviors. The U.S. Centers for Disease Control and Management says that one in 88 children in the US is somewhere on the Autism spectrum — an alarming ten-fold increase in the last four decades.

New research by Dr. Mark Weiser of Tel Aviv University’s Sackler Faculty of Medicine and the Sheba Medical Center has revealed that ASD appears share a root cause with other mental illnesses, including schizophrenia and bipolar disorder. At first glance, schizophrenia and autism may look like completely different illnesses, he says. But closer inspection reveals many common traits, including social and cognitive dysfunction and a decreased ability to lead normal lives and function in the real world.

Studying extensive databases in Israel and Sweden, the researchers discovered that the two illnesses had a genetic link, representing a heightened risk within families. They found that people who have a schizophrenic sibling are 12 times more likely to have autism than those with no schizophrenia in the family. The presence of bipolar disorder in a sibling showed a similar pattern of association, but to a lesser degree.

A scientific leap forward, this study sheds new light on the genetics of these disorders. The results will help scientists better understand the genetics of mental illness, says Dr. Weiser, and may prove to be a fruitful direction for future research. The findings have been published in the Archives of General Psychiatry.

All in the family

Researchers used three data sets, one in Israel and two in Sweden, to determine the familial connection between schizophrenia and autism. The Israeli database alone, used under the auspices of the ethics committees of both the Sheba Medical Center and the Israeli Defense Forces, included anonymous information about more than a million soldiers, including patients with schizophrenia and ASD.

"We found the same results in all three data sets," he says, noting that the ability to replicate the findings across these extensive databases is what makes this study so significant.Understanding this genetic connection could be a missing link, Dr. Weiser says, and provides a fresh direction for study. The researchers are now taking this research in a clinical direction. For now, though, the findings shouldn’t influence the way that doctors treat patients with either illness, he adds.

People with perfect pitch seem to possess their own inner pitch pipe, allowing them to sing a specific note without first hearing a reference tone. This skill has long been associated with early and extensive musical training, but new research suggests that perfect pitch may have as much to do with genetics as it does with learning an instrument or studying voice.

Previous research does draw a connection between early musical training and the likelihood of a person developing perfect pitch, which is also referred to as absolute pitch. This is especially true among speakers of tonal languages, such as Mandarin. Speakers of English and other non-tonal languages are far less likely to develop perfect pitch, even if they were exposed to early and extensive musical training.

“We have wondered if perfect pitch is as much about nature or nurture,” said Diana Deutsch, a professor of psychology at the University of California, San Diego. “What is clear is that musically trained individuals who speak a non-tone language can acquire absolute pitch, but it is still a remarkably rare talent. What has been less clear is why most others with equivalent musical training do not.” Deutsch and her colleague Kevin Dooley present their findings at the 164th meeting of the Acoustical Society of America (ASA), held Oct. 22 – 26 in Kansas City, Missouri.

To shine light on this question, the researchers studied 27 English speaking adults, 7 of whom possessed perfect pitch. All began extensive musical training at or before the age of 6. The researchers tested the subjects’ memory ability using a test known as the digit span, which measures how many digits a person can hold in memory and immediately recall in correct order. They presented the digits either visually or auditorily; for the auditory test, the subject listened to the numbers through headphones, and for the visual test the digits were presented successively at the center of a computer screen.

The people with perfect pitch substantially outperformed the others in the audio portion of the test. In contrast, for the visual test, the two groups exhibited very similar performance, and their scores were not significantly different from each other. This is significant because other researchers have shown previously that auditory digit span has a genetic component.

“Our finding therefore shows that perfect pitch is associated with an unusually large memory span for speech sounds,” said Deutsch, “which in turn could facilitate the development of associations between pitches and their spoken languages early in life.”

A new study shows that electrical stimulation of a small patch of the brain causes illusions that only affect the perception of faces. (Matt Cardy/Getty Images)

Ron Blackwell didn’t enter the hospital expecting to see his doctor’s face melt before his eyes. But that’s exactly what happened when researchers electrically stimulated a small part of his brain, according to a study published Tuesday in the Journal of Neuroscience.

The doctor’s face did not actually melt, of course. Instead, the researchers argue, the stimulation short-circuited a brain area called the fusiform gyrus. Previous studies have linked a part of that area to face processing by showing that it becomes active when people perceive faces. But it’s hard to know just how important the area is for facial processing unless you can actually change its activity level while someone views faces.

Blackwell, an epileptic, turned out to be the perfect test case. He was in Stanford’s hospital so that doctors — including the study author, Dr. Josef Parvizi — could study his epilepsy and decide whether they could perform surgery to remove the part of the brain responsible for his seizures. As part of that procedure, Parvizi laid down a strip of electrodes on the surface of the brain. That gave him the capacity to painlessly and harmlessly stimulate the part of the brain they covered, and one of those electrodes was right over the fusiform gyrus.

Along with collaborators led by Stanford psychologist Kalanit Grill-Spector, Parvizi stimulated the area to see whether it would affect Blackwell’s perception of the doctor’s face. When he performed a sham stimulation — counting down from three and pressing a button that did nothing — Blackwell reported no change.

But when Parvizi applied voltage, strange things suddenly began to happen to Blackwell’s face perception. “You just turned into somebody else,” Blackwell said in a video that was recorded as part of the experiment. “Your face metamorphosed. Your nose got saggy, went to the left. You almost looked like somebody I’d seen before, but somebody different. That was a trip.” As soon as the electricity was turned off, Blackwell’s visualization of Parvizi’s face returned to normal.

Later, Blackwell confirmed that it was only the doctor’s face that changed — his body and hands remained the same.

Though only a single case, the experiment provides strong confirmatory evidence that the fusiform gyrus is indeed directly involved in processing face perception, and that the area is specialized for doing so.

New imaging techniques are mapping the locations of our aesthetic response

In Michelangelo’s Expulsion from Paradise, a fresco panel on the ceiling of the Sistine Chapel, the fallen-from-grace Adam wards off a sword-wielding angel, his eyes averted from the blade and his wrist bent back defensively. It is a gesture both wretched and beautiful. But what is it that triggers the viewer’s aesthetic response—the sense that we’re right there with him, fending off blows?

Recently, neuroscientists and an art historian asked ten subjects to examine the wrist detail from the painting, and—using a technique called trans­cranial magnetic stimulation (TMS)—monitored what happened in their brains. The researchers found that the image excited areas in the primary motor cortex that controlled the observers’ own wrists.

“Just the sight of the raised wrist causes an activation of the muscle,” reports David Freedberg, the Columbia University art history professor involved in the study. This connection explains why, for instance, viewers of Degas’ ballerinas sometimes report that they experience the sensation of dancing—the brain mirrors actions depicted on the canvas.

Freedberg’s study is part of the new but growing field of neuroaesthetics, which explores how the brain processes a work of art. The discipline emerged 12 years ago with publication of British neuroscientist Semir Zeki’s book, Inner Vision: An Exploration of Art and the Brain. Today, related studies depend on increasingly sophisticated brain-imaging techniques, including TMS and functional magnetic resonance imaging (fMRI), which maps blood flow and oxygenation in the brain. Scientists might monitor an observer’s reaction to a classical sculpture, then warp the sculpture’s body proportions and observe how the viewer’s response changes. Or they might probe what occurs when the brain contemplates a Chinese landscape painting versus an image of a simple, repetitive task.

Ulrich Kirk, a neuroscientist at the Virginia Tech Carilion Research Institute, is also interested in artworks’ contexts. Would a viewer respond the same way to a masterpiece enshrined in the Louvre if he beheld the same work displayed in a less exalted setting, such as a garage sale? In one experiment, Kirk showed subjects a series ofimages—some, he explained, were fine artwork; others were created by Photoshop. In reality, none were Photoshop-generated; Kirk found that different areas of viewers’ brains fired up when he declared an image to be “art.”

Kirk also hopes one day to plumb the brains of artists themselves. “You might be able to image creativity as it happens, by putting known artists in the fMRI,” he says.

Others, neuroscientists included, worry that neuroscience offers a reductionist perspective. Vilayanur Ramachandran, a neuroscientist at the University of California at San Diego, says that neuro­aesthetics undoubtedly “enriches our understanding of human aesthetic experience.” However, he adds, “We have barely scratched the sur­face…the quintessence of art, and of genius, still eludes us—and may elude us forever.”

Analysis of specific biomarkers in a cerebrospinal fluid sample can differentiate patients with Alzheimer’s disease from those with other types of dementia. The method, which is being studied by researchers at Sahlgrenska Academy, may eventually permit earlier detection of Alzheimer’s disease.

Due to the similarity of the symptoms, differentiating patients with Alzheimer’s from those with other types of dementia – or patients with Parkinson disease from those with other motor disorders – is often difficult.

Making a proper diagnosis is essential if proper treatment and medication are to commence at an early stage. A research team at Sahlgrenska Academy, University of Gothenburg, is developing a new method to differentiate patients with Alzheimer’s disease or Parkinson disease by analyzing a cerebrospinal fluid sample.

The study, led by Professor Kaj Blennow and conducted among 450 patients at Skåne University Hospital and Sahlgrenska University Hospital, involved testing five proteins that serve as biomarkers for the two diseases.

“Previous studies have shown that Alzheimer’s disease is associated with biochemical changes in specific proteins of the brain,” says Annika Öhrfelt, a researcher at Sahlgrenska Academy. “This study has found that the inclusion of a new protein can differentiate patients with Alzheimer’s disease from those with Lewy body dementia, Parkinson disease dementia and other types of dementia.”

Similarly, the biomarkers can differentiate patients with Parkinson disease from those with atypical Parkinsonian disorders.

“Additional studies are needed before the biomarkers can be used in clinical practice during the early stages of disease,” says Öhrfelt, “but these results represent an important step along the way.”

Researchers at Washington University School of Medicine in St. Louis have found a key difference in the brains of people with Alzheimer’s disease and those who are cognitively normal but still have brain plaques that characterize this type of dementia.

“There is a very interesting group of people whose thinking and memory are normal, even late in life, yet their brains are full of amyloid beta plaques that appear to be identical to what’s seen in Alzheimer’s disease,” says David L. Brody, MD, PhD, associate professor of neurology. “How this can occur is a tantalizing clinical question. It makes it clear that we don’t understand exactly what causes dementia.”

Hard plaques made of a protein called amyloid beta are always present in the brain of a person diagnosed with Alzheimer’s disease, according to Brody. But the simple presence of plaques does not always result in impaired thinking and memory. In other words, the plaques are necessary – but not sufficient – to cause Alzheimer’s dementia.

The new study, available online in Annals of Neurology, still implicates amyloid beta in causing Alzheimer’s dementia, but not necessarily in the form of plaques. Instead, smaller molecules of amyloid beta dissolved in the brain fluid appear more closely correlated with whether a person develops symptoms of dementia. Called amyloid beta “oligomers,” they contain more than a single molecule of amyloid beta but not so many that they form a plaque.

Oligomers floating in brain fluid have long been suspected to have a role in Alzheimer’s disease. But they are difficult to measure. Most methods only detect their presence or absence, or very large quantities. Brody and his colleagues developed a sensitive method to count even small numbers of oligomers in brain fluid and used it to compare amounts in their samples.

The researchers examined samples of brain tissue and fluid from 33 deceased elderly subjects (ages 74 to 107). Ten subjects were normal – no plaques and no dementia. Fourteen had plaques, but no dementia. And nine had a diagnosis of Alzheimer’s disease – both plaques and dementia.

They found that cognitively normal patients with plaques and Alzheimer’s patients both had the same amount of plaque, but the Alzheimer’s patients had much higher oligomer levels.

But even oligomer levels did not completely distinguish the two groups. For example, some people with plaques but without dementia still had oligomers, even in similar quantity to some patients with Alzheimer’s disease. Where the two groups differed completely, according to Brody and his colleagues, was the ratio of oligomers to plaques. They measured more oligomers per plaque in patients with dementia, and fewer oligomers per plaque in the samples from cognitively normal people.

In people with plaques but no dementia, Brody speculates that the plaques could serve as a buffer, binding with free oligomers and keeping them tied down. And in dementia, perhaps the plaques have exceeded their capacity to capture the oligomers, leaving them free to float in the brain’s fluid, where they can damage or interfere with neurons.

Brody cautions that, due to the difficulty in getting samples, oligomer levels have never been measured in living people. Therefore, it’s possible these floating clumps of amyloid beta only form after death. Even so, he says, there is still a clear difference between the two groups.

“The plaques and oligomers appear to be in some kind of equilibrium,” Brody says. “What happens to shift the relationship between the oligomers and plaques? Like much Alzheimer’s research, this study raises more questions than it answers. But it’s an important next piece of the puzzle.”

Blood-circulating immune cells can take over the essential immune surveillance of the brain, this is shown by scientists of the German Center for Neurodegenerative Diseases (DZNE) and the Hertie Institute for Clinical Brain Research in Tübingen. Their study, now published in PNAS, might indicate new ways of dealing with diseases of the nervous system.

The immune system is comprised of multiple cell types each capable of specialized functions to protect the body from invading pathogens and promote tissue repair after injury. One cell type, known as monocytes, circulates throughout the organism in the blood and enters tissues to actively phagocytose (eat!) foreign cells and assist in tissue healing. While monocytes can freely enter most bodily tissues, the healthy, normal brain is different as it is sequestered from circulating blood by a tight network of cells known as the blood brain barrier. Thus, the brain must maintain a highly specialized, resident immune cell, known as microglia, to remove harmful invaders and respond to tissue damage.

In certain situations, such as during disease, monocytes can enter the brain and also contribute to tissue repair or disease progression. However, the potential for monocytes to actively replace old or injured microglia is under considerable debate. To address this, Nicholas Varvel, Stefan Grathwohl and colleagues from the German Center for Neurodegenerative Diseases (DZNE) Tübingen and the Hertie Institute for Clinical Brain Research in Tübingen used a transgenic mouse model in which almost all brain microglia cells (>95%) can be removed within two weeks. This was done by introducing a so-called suicide gene into microglia cells and administering a pharmaceutical agent that leads to acute death of the cells. Surprisingly, after the ablation of the microglia, the brain was rapidly repopulated by blood-circulating monocytes. The monocytes appeared similar, but not identical to resident microglia. The newly populated monocytes, evenly dispersed throughout the brain, responded to acute neuronal injury and other stimuli — all activities normally assumed by microglia. Most interestingly, the monocytes were still present in the brain six months - nearly a quarter of the life of a laboratory mouse - after initial colonization.

These studies now published in PNAS provide evidence that blood-circulating monocytes can replace brain resident microglia and take over the essential immune surveillance of the brain. Furthermore, the findings highlight a strong homeostatic mechanism to maintain a resident immune cell within the brain. The observation that the monocytes took up long-term residence in the brain raises the possibility that these cells can be utilized to deliver therapeutic agents into the diseased brain or replace microglia when they become dysfunctional. Can monocytes be exploited to combat the consequences of Alzheimer’s disease and other neurodegenerative diseases? The scientists and their colleagues in the research groups headed by Mathias Jucker are now following exactly this research avenue.

In 1906, when Alois Alzheimer discovered the neurodegenerative disease that would later be named for him, he saw amyloid-beta plaques and neurofibrillary tangles inside the brain. Several decades later, abnormal protein structures called Hirano bodies also were frequently observed in patients with neurodegenerative diseases.

A hundred years and many millions of suffering patients and families later, scientists still don’t know what these structures do. They do know, thanks to new research from the University of Georgia, that Hirano bodies may have a protective role in the brain of Alzheimer’s patients.

Matthew Furgerson, a doctoral candidate in the UGA Franklin College of Arts and Sciences department of biochemistry and molecular biology, used cell culture models to study the role of Hirano bodies in cell death induced by AICD, or a fragment of AICD called c31, that are released inside the cell during cleavage of the amyloid precursor protein. This cleavage also produces amyloid-beta, which forms extracellular plaques.

Furgerson found mixtures of amyloid precursor protein, c31 and tau-the protein that forms the intracellular neurofibrillary tangles-or of AICD and tau cause synergistic cell death that is significantly higher than cell death from amyloid precursor protein, c31, AICD or tau alone.

"This synergistic cell death is very exciting," Furgerson said. "Other groups have shown synergy between extracellular amyloid beta or amyloid precursor protein with tau, but these new results show that there may be an important interaction that occurs inside the cells."

The results of this study were published in the September issue of PLoS One. Ruth Furukawa, associate research scientist, and Marcus Fechheimer, University Professor in cellular biology, are co-authors on the paper.

Furgerson also found cell death is significantly reduced in cells that contain Hirano bodies compared to cells without Hirano bodies. The protective effect of Hirano bodies was observed in cell cultures in both the presence and absence of tau. The findings reveal that Hirano bodies may have a protective role during the progression of Alzheimer’s disease.

While this research offers no cure for the disease, it does offer some understanding about how the disease operates. The lab has been a leader of Hirano body research for more than a decade due to their development of cell culture and mouse model systems.

Before the development of model systems, the only way to study these abnormal structures was in post-mortem brain tissue. The recently developed Hirano body mouse model is currently being used with an Alzheimer’s model mouse to investigate whether cell culture results can translate to a complex animal.

"I feel privileged to lead a team that might be able to contribute knowledge to help us understand Alzheimer’s disease processes," Fechheimer said. "Other groups have focused on plaques and tangles, and we don’t know as much about Hirano bodies. Results from the cell culture studies are exciting and reveal the protective role of Hirano bodies. Our ongoing studies with mouse models are essential to defining the role of Hirano bodies in Alzheimer’s disease progression in a whole animal."