Posts tagged neurodegenerative diseases
Articles and news from the latest research reports.
Bacteria yield clues about why proteins go bad in ALS and Alzheimer’s
Scientists are unsure why proteins form improperly and cluster together in bunches, a hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s and Mad Cow Disease. In the Nov. 1 issue of the journal Molecular Cell, Yale scientists shed light on protein aggregate formation by studying the process in bacteria.
“The question we are all asking is what happens when protein synthesis goes wrong?” said Jesse Rinehart, assistant professor of cellular and molecular physiology at Yale’s West Campus and co-senior author of the paper.
Proteins are created from instructions encoded in DNA and assembled in ribosomes within the cells. However, sometimes they are not assembled correctly, and these misfolded proteins tend to aggregate, a process typified by the plaques that form in the brains of Alzheimer’s patients.
The Yale team — led by Rinehart and Dieter Söll, Sterling Professor of Molecular Biophysics and Biochemistry and professor of chemistry — showed that the antibiotic streptomycin can trigger protein aggregations in the bacterium E. coli. Using large-scale proteomics and genetic screens, they analyzed the aggregates and searched for bacterial proteins that make E. coli cells resistant to antibiotics and other threats. The researchers discovered how one of these proteins protecting the bacteria from hydrogen peroxide also suppressed the aggregation of proteins triggered by streptomycin.
The endocannabinoid system in normal and pathological brain ageing
The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.
Primates’ brains make visual maps using triangular grids
Primates’ brains see the world through triangular grids, according to a new study published online Sunday in the journal Nature.
Scientists at Yerkes National Primate Research Center, Emory University, have identified grid cells, neurons that fire in repeating triangular patterns as the eyes explore visual scenes, in the brains of rhesus monkeys.
The finding has implications for understanding how humans form and remember mental maps of the world, as well as how neurodegenerative diseases such as Alzheimer’s erode those abilities. This is the first time grid cells have been detected directly in primates. Grid cells were identified in rats in 2005, and their existence in humans has been indirectly inferred through magnetic resonance imaging.
Grid cells’ electrical activities were recorded by introducing electrodes into monkeys’ entorhinal cortex, a region of the brain in the medial temporal lobe. At the same time, the monkeys viewed a variety of images on a computer screen and explored those images with their eyes. Infrared eye-tracking allowed the scientists to follow which part of the image the monkey’s eyes were focusing on. A single grid cell fires when the eyes focus on multiple discrete locations forming a grid pattern.
"The entorhinal cortex is one of the first brain regions to degenerate in Alzheimer’s disease, so our results may help to explain why disorientation is one of the first behavioral signs of Alzheimer’s," says senior author Elizabeth Buffalo, PhD, associate professor of neurology at Emory University School of Medicine and Yerkes National Primate Research Center. "We think these neurons help provide a context or structure for visual experiences to be stored in memory."
"Our discovery of grid cells in primates is a big step toward understanding how our brains form memories of visual information," says first author Nathan Killian, a graduate student in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. "This is an exciting way of thinking about memory that may lead to novel treatments for neurodegenerative diseases."
(Image credit: Mark Snelson)
Parkinson’s breakthough could slow disease progression
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.
(Source: eurekalert.org)
Challenging Parkinson’s Dogma: Dopamine may not be the only key player in this tragic neurodegenerative disease
Scientists may have discovered why the standard treatment for Parkinson’s disease is often effective for only a limited period of time. Their research could lead to a better understanding of many brain disorders, from drug addiction to depression, that share certain signaling molecules involved in modulating brain activity.
A team led by Bernardo Sabatini, Takeda Professor of Neurobiology at Harvard Medical School, used mouse models to study dopamine neurons in the striatum, a region of the brain involved in both movement and learning. In people, these neurons release dopamine, a neurotransmitter that allows us to walk, speak and even type on a keyboard. When those cells die, as they do in Parkinson’s patients, so does the ability to easily initiate movement. Current Parkinson’s drugs are precursors of dopamine that are then converted into dopamine by cells in the brain.
The flip side of dopamine dearth is dopamine hyperactivity. Heroin, cocaine and amphetamines rev up or mimic dopamine neurons, ultimately reinforcing the learned reward of drug-taking. Other conditions such as obsessive-compulsive disorder, Tourette syndrome and even schizophrenia may also be related to the misregulation of dopamine.
In the October 11 issue of Nature, Sabatini and co-authors Nicolas Tritsch and Jun Ding reported that midbrain dopamine neurons release not only dopamine but also another neurotransmitter called GABA, which lowers neuronal activity. The previously unsuspected presence of GABA could explain why restoring only dopamine could cause initial improvements in Parkinson’s patients to eventually wane. And if GABA is made by the same cells that produce other neurotransmitters, such as depression-linked serotonin, similar single-focus treatments could be less successful for the same reason.
“If what we found in the mouse applies to the human, then dopamine’s only half the story,” said Sabatini.
New Dementia Diagnostic Exams and Gene Findings Bode Well for Treatment
The number of people affected by dementias continues to climb as baby boomers age, increasing the urgency to identify ways to prevent, diagnose and treat these neurodegenerative brain disorders.
Today it is possible to diagnose dementias more accurately than ever before, thanks to improvements in behavioral assessment tools, imaging techniques, gene testing and data collection and analysis, according to Bruce L. Miller, MD, a behavioral neurologist and professor of neurology at UCSF.
Miller, who came to UCSF in 1998 and directs the UCSF Memory and Aging Center, described recent advances during the lecture he gave at UCSF Mission Bay on Oct. 15 as part of receiving the Academic Senate’s 12th Annual Faculty Research Lectureship in Clinical Science.
The ability to diagnose different types of dementias accurately and to distinguish among the biological factors that cause them will become increasingly important as treatments become more promising and better targeted, Miller said.
Despite continued improvements in the tools available to physicians for diagnosing dementias, a common neurodegenerative disease known as frontotemporal dementia (FTD) remains understudied and is very often misdiagnosed, Miller said. For reasons that are in part historical, FTD still is thought of as a rare disease, a misconception that greatly contributes to its being underdiagnosed, he said. While Alzheimer’s disease is the most common dementia overall, among the population aged 65 and younger, FTD is just as common, according to Miller.
Immune cells of the blood might replace dysfunctional brain cells
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.
(Source: dzne.de)
UGA discovery sheds light on Alzheimer’s mystery
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."
(Source: news.uga.edu)
Study identifies natural process activating brain’s immune cells that could point way to repairing damaged brain
The brain’s key “breeder” cells, it turns out, do more than that. They secrete substances that boost the numbers and strength of critical brain-based immune cells believed to play a vital role in brain health. This finding adds a new dimension to our understanding of how resident stem cells and stem cell transplants may improve brain function.
Many researchers believe that these cells may be able to regenerate damaged brain tissue by integrating into circuits that have been eroded by neurodegenerative disease or destroyed by injury. But new findings by scientists at the Stanford University School of Medicine suggest that another process, which has not been fully appreciated, could be a part of the equation as well. The findings appear in a study published online Oct. 21 in Nature Neuroscience.
“Transplanting neural stem cells into experimental animals’ brains shows signs of being able to speed recovery from stroke and possibly neurodegenerative disease as well,” said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences in the medical school and senior research scientist at the Veterans Affairs Palo Alto Health Care System. “Why this technique works is far from clear, though, because actually neural stem cells don’t engraft well.”
Yamanaka invented cell time machine
Dr. Shinya Yamanaka invented a time machine.
In the simplest of terms, that’s how he and his colleagues sometimes describe their work. They take full-grown cells from humans and they regress them - they send them back in time, to their earliest, embryonic state - and then they coax them into the future, into totally new types of cells.
Last week, Yamanaka was awarded the Nobel Prize in physiology or medicine for his work creating induced pluripotent stem (IPS) cells - cells that are genetically engineered into blank slates, allowing them to be transformed into any type of cell in the body.
His technique could allow scientists to explore human diseases like they never have before, or help doctors regenerate tissue lost to injury or illness. Using his technology, scientists can now take a skin cell and transform it into a heart cell that will actually beat in a lab dish.
"I was here, at Gladstone, the moment I learned we got human IPS cells," said Yamanaka last month, in an interview from his part-time office at San Francisco’s Gladstone Institutes. Yamanaka did most of the IPS cell work at his main lab in Japan.
"My colleague sent me the image, and it was, wow," Yamanaka said, offering a brief, modest smile. "We had beating human heart cells, made from IPS cells."