Posts tagged science
Articles and news from the latest research reports.
Discovery of molecular pathway of Alzheimer’s disease reveals new drug targets
The discovery of the molecular pathway that drives the changes seen in the brains of Alzheimer’s patients is reported today, revealing new targets for drug discovery that could be exploited to combat the disease. The study gives the most detailed understanding yet of the complex processes leading to Alzheimer’s.
Alzheimer’s disease is associated with plaques made up of deposits of a molecule called amyloid between brain cells, which leads to the formation of tangles of twisted fibres made from a molecule called tau, found inside the brain cells. This causes the death of brain cells which is thought to bring about the symptoms of memory loss and dementia. Although it has been accepted for over twenty years that the progression of disease is driven by amyloid and results in abnormal changes in tau, the exact mechanisms of disease remain somewhat of a mystery.
Recent genome wide association studies have identified the gene for a molecule called clusterin as a susceptibility factor for late-onset Alzheimer’s disease. Levels of clusterin are also known to be elevated in blood in patients with Alzheimer’s from an early stage in the disease so the researchers wanted to find out what role it might play in the progression of disease.
The team, led by researchers at King’s College London’s Institute of Psychiatry, looked first in mouse brain cells grown in the laboratory and found that the presence of amyloid alters the amount of clusterin in these cells. Clusterin then acts to switch on a signalling pathway that drives the changes in tau that are associated with the formation of tangles inside the cells, another hallmark of the disease. When this signalling pathway was chronically switched on in a mouse model of the disease, the researchers observed an increase in tangle formation and evidence of cognitive defects.
The study, published in the journal Molecular Psychiatry, also looked in humans and detected the signature of clusterin activation in the brains of Alzheimer’s patients but not in the brains of patients with other forms of dementia.
Dr Richard Killick from King’s College London’s Institute of Psychiatry said: “This is the first time we’ve been able to connect the molecular mechanisms behind the formation of amyloid plaques in the brain with the formation of tangles inside the brain cells, two of the defining features of Alzheimer’s disease. Our research has given the most detailed picture yet of how the disease progresses and we hope it will offer leads for the development of new treatments.”
The signalling pathway that is turned on by clusterin is called DKK1-WNT. It involves interactions between a number of different molecules that could prove to be useful targets for the development of new drugs.
Current treatments for Alzheimer’s are focused on alleviating the symptoms and there is no therapy that can prevent the progression of disease.
Professor Simon Lovestone, also from King’s College London’s Institute of Psychiatry, who led the study, said: “We have shown that we can block the toxic effects of amyloid when we stop this signalling pathway in brain cells grown in the lab. We believe that if we could block its activity in the brains of Alzheimer’s patients too, we may have an opportunity to halt the disease in man. Indeed, we have already begun our own drug development programme to do just that and are at the stage where potential compounds are coming back to us for further testing.”
The DKK1-WNT pathways has also been implicated in some human cancers and although there is no evidence for a direct link, the findings from this study mean that there could be an opportunity to make advances in Alzheimer’s research by capitalising on knowledge that is being gained from cancer research, the authors suggest.
Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, which helped fund this study, said: “We will see more and more people affected by Alzheimer’s disease as our population ages. This study gives us a much-needed additional insight to the complex biology that contributes to the development of Alzheimer’s, which is vital if we are to develop new treatments that are so urgently needed.”
(Source: eurekalert.org)
Research shows diabetes drug improves memory
An FDA-approved drug initially used to treat insulin resistance in diabetics has shown promise as a way to improve cognitive performance in some people with Alzheimer’s disease.
Working with genetically engineered mice designed to serve as models for Alzheimer’s, University of Texas Medical Branch at Galveston researchers found that treatment with the anti-insulin-resistance drug rosiglitazone enhanced learning and memory as well as normalized insulin resistance. The scientists believe that the drug produced the response by reducing the negative influence of Alzheimer’s on the behavior of a key brain-signaling molecule.
The molecule, called extracellular signal-regulated kinase (ERK), becomes hyperactive both in the brains of Alzheimer’s patients and in the mice at a disease stage corresponding to mild cognitive impairment in human Alzheimer’s. This excessive activity leads to improper synaptic transmission between neurons, interfering with learning and memory.
Rosiglitazone brings ERK back into line by activating what’s known as the peroxisome proliferator-activated receptor gamma (PPARγ) pathway, which interacts with genes that respond to both PPARγ and ERK.
“Using this drug appears to restore the neuronal signaling required for proper cognitive function,” said UTMB professor Larry Denner, the lead author of a paper describing this work now online (posted Nov. 21) in the Journal of Neuroscience. “It gives us an opportunity to test several FDA-approved drugs to normalize insulin resistance in Alzheimer’s patients and possibly also enhance memory, and it also gives us a remarkable tool to use in animal models to understand the molecular mechanisms that underlie cognitive issues in Alzheimer’s.”
Discovery offers new treatment for epilepsy
New drugs derived from components of a specific diet used by children with severe, drug-resistant epilepsy could offer a new treatment, according to research published today in the journal Neuropharmacology.
Scientists from Royal Holloway, in collaboration with University College London, have identified specific fatty acids that have potent antiepileptic effects, which could help control seizures in children and adults.
The discovery could lead to the replacement of the ketogenic diet, which is often prescribed for children with severe drug-resistant epilepsy. The high fat, low carbohydrate diet is thought to mimic aspects of starvation by forcing the body to burn fats rather than carbohydrates. Although often effective, the diet has attracted criticism, as side effects can be significant and potentially lead to constipation, hypoglycaemia, retarded growth and bone fractures.
By pinpointing fatty acids in the ketogenic diet that are effective in controlling epilepsy, researchers hope that they can develop a pill for children and adults that could provide similar epilepsy control, but lacks the side effects of the diet.
Professor Robin Williams from the Centre of Biomedical Sciences at Royal Holloway said: “This is an important breakthrough. The family of medium chain fatty acids that we have identified provide an exciting new field of research with the potential of identifying, stronger, and safer epilepsy treatments.”
The study tested a range of fatty acids found in the ketogenic diet against an established epilepsy treatment. Researchers found that not only did some of the fatty acids outperform the drug in controlling seizures, they also had fewer side effects.
(Source: alphagalileo.org)
New noninvasive tool helps target Parkinson’s disease
Health professionals may soon have a new method of diagnosing Parkinson’s disease, one that is noninvasive and inexpensive, and, in early testing, has proved to be effective more than 90 percent of the time.
In addition, this new method has the potential to track the progression of Parkinson’s, as well as measure the effectiveness of treatments for the disorder, said Rahul Shrivastav, professor and chairperson of Michigan State University’s Department of Communicative Sciences and Disorders and a member of the team developing the new method.
It involves monitoring a patient’s speech patterns – specifically, movement patterns of the tongue and jaw.
“In Parkinson’s disease, a common limitation is that the movements become slow and have a reduced range,” said Shrivastav. “We believe we see this pattern in speech too – the tongue doesn’t move as far as it should, doesn’t move as quickly as it should and produces subtle changes in speech patterns.”
This method is particularly sensitive to Parkinson’s disease speech and, Shrivastav said, is effective with only two seconds of speech.
“That’s significant in several ways: The detection methodology is noninvasive, easy to administer, inexpensive and capable of being used remotely and in telemedicine applications,” he said.
Presently there are no tried-and-true methods for diagnosing Parkinson’s. Shrivastav said if a person is showing early symptoms of the disease, which include tremors, slower movements or rigid muscles, he or she is given a drug to treat the disease.
“If the symptoms go away,” he said, “then it’s assumed you must have Parkinson’s disease.”
In more advanced cases, he said, symptoms are usually prominent enough that it is fairly easy to diagnose.
Parkinson’s disease is a neurological disorder affecting a half million people in the United States, with 50,000 newly diagnosed cases every year. It occurs when nerve cells in the brain stop producing a chemical called dopamine, which helps control muscle movement. Without dopamine, the nerve cells cannot properly send messages, leading to the loss of muscle function.
While there is no cure for Parkinson’s disease, early detection is particularly important since the treatments currently available for controlling symptoms are most effective at that stage.
(Source: news.msu.edu)
The evolution of human intellect: Human-specific regulation of neuronal genes
A new study published November 20 in the open-access journal PLOS Biology has identified hundreds of small regions of the genome that appear to be uniquely regulated in human neurons. These regulatory differences distinguish us from other primates, including monkeys and apes, and as neurons are at the core of our unique cognitive abilities, these features may ultimately hold the key to our intellectual prowess (and also to our potential vulnerability to a wide range of ‘human-specific’ diseases from autism to Alzheimer’s).
Exploring which features in the genome separate human neurons from their non-human counterparts has been a challenging task until recently; primate genomes comprise billions of base pairs (the basic building blocks of DNA), and comparisons between the human and chimpanzee genomes alone reveal close to 40 million differences. Most of these are thought to merely reflect random ‘genetic drift’ during the course of evolution, so the challenge was to identify the small set of changes that have functionally important consequences, as these might help to explain the genomic basis of the emergence of human-specific neuronal function.
The key to the present study, led by Dr Schahram Akbarian of the University of Massachusetts and the Mount Sinai School of Medicine, was not to focus on the “letters” of the DNA code, but rather on what might be called its “font” or “typeface”—the DNA strands of the genome are wrapped in protein to make a chromatin fiber, and the way in which they are wrapped, the “chromatin state”, in turn reflects the regulatory state of that region of the genome (e.g. whether a given gene is turned on or off). This is the field that biologists call “epigenetics”—the study of the “epigenome”.
Dr Akbarian and colleagues set out to isolate small snippets of chromatin fibers from the frontal cortex, a brain region involved in complex cognitive operations. They were then able to analyze these snippets for the chemical signals (histone methylation) that define the regulatory state (on/off) of the chromatin. The results of their analysis identified hundreds of regions throughout the genome which showed a markedly different chromatin structure in neurons from human children and adults, compared to chimpanzees and macaques.
This treasure trove of short genomic regions is now providing researchers with interesting new leads involving the evolution of the human brain. Although some of the regions have remained unchanged during primate evolution, some more tantalizing ones have recently changed, having a DNA sequence that is unique to humans and our close extinct relatives, the Neanderthals and the Denisovans.
The study also uncovered examples where several of these regulatory DNA regions appear to physically interact with each other inside the cell nucleus, despite being separated by hundreds of thousands of base pairs on the linear genome. This phenomenon of “chromatin looping” is implicated in controlling the expression of neighboring genes, including several with a critical role for human brain development. The study, from laboratories based in the United States, Switzerland and Russia, draws further attention to the role of epigenetics and the epigenome in our biology and our evolution. As Dr Akbarian notes, “Much about human biology and disease cannot be deduced by simply sequencing the genome. Mapping the epigenome of neurons and other cells will help us to better understand the inner workings of our brain, and where we are coming from.”
(Source: medicalxpress.com)
Primate Behavior May Reveal Clues to Evolution of Favor Exchange in Humans
When your neighbor asks to borrow a cup of sugar and you readily comply, is your positive response a function of the give and take that characterize your longstanding relationship? Or does it represent payment –– or prepayment –– for the cup of sugar you borrowed last week, or may need to borrow a month from now?
Adrian Jaeggi, a postdoctoral researcher in anthropology at UC Santa Barbara, and a junior research fellow at the campus’s SAGE Center for the Study of the Mind, is studying this question of reciprocity, using chimpanzees and bonobos as his test subjects. His findings appear in the current online issue of the journal Evolution & Human Behavior.
"The article focuses on the question of whether individuals do favors because they expect them to be reciprocated at some other time, and, more specifically, whether such exchanges have to happen immediately, or can take place over longer time spans," Jaeggi explained. "We studied the question in chimpanzees and bonobos –– our two closest living relatives –– and looked at the exchanges of grooming and food sharing, which are two common types of favors among these apes."
According to Jaeggi, while results of his research provide some evidence for immediate exchanges, they more strongly support the notion that favors are exchanged over long periods of time. Calculated exchanges, in which individuals keep a detailed score of past interactions, are much less common than the more loosely balanced exchanges that take place in stable relationships.
Optical Illusions Show How We See
Imagine… as you wake later than usual rolling over towards the window, you notice that it’s a gorgeous day outside. Warm, yellow sunlight shines in through glass illuminating floating “dust angles.” On the other side of the glass, past the oak tree with yellowing leaves, you see a brilliant blue sky. For the first time it occurs to you that a blue sky is a contradiction: the sky at night is devoid of color, so why during the day does the world seem to be shrouded in a blanket of blue? Years previously as a child full of questions you asked your parents, but the answer they offered seemed somehow inadequate at the time… less than magical. And so the question remains… as it does the most of us.
The answer is this: The sky isn’t actually colored at all (not blue or yellow or red or green). Rather, it’s your mind that’s colored. The world around us is physics devoid of meaning, whereas our perception of the world is meaning devoid of physics. In terms of physics, the light in the sky is heavily biased towards smaller wavelengths (around 450 nanometers). This is because the air itself scatters smaller wavelengths of light more than it does larger ones. Which means the air in the sky is like a filter, letting primarily medium to long wavelengths through more easily than short wavelengths. Hence why the sky is composed primarily of shorter wavelengths (and so appears bluish), whereas the light from sun is composed primarily of longer wavelengths (and so appears more reddish). While the differential scattering of sunlight by the air explains the non-uniform distribution of wavelengths across the sky, it doesn’t explain why shorter wavelengths are seen as blue and the longer ones as red.
'Different kind of stem cell' possesses attributes favoring regenerative medicine
A research team at Georgetown Lombardi Comprehensive Cancer Center say the new and powerful cells they first created in the laboratory a year ago constitute a new stem-like state of adult epithelial cells. They say these cells have attributes that may make regenerative medicine truly possible.
In the November 19 online early edition of the Proceedings of the National Academy of Sciences (PNAS), they report that these new stem-like cells do not express the same genes as embryonic stem cells and induced pluripotent stem cells (iPSCs) do. That explains why they don’t produce tumors when they grow in the laboratory, as the other stem cells do, and why they are stable, producing the kind of cells researchers want them to.
"These seem to be exactly the kind of cells that we need to make regenerative medicine a reality," says the study’s senior investigator, chairman of the department of pathology at Georgetown Lombardi, a part of Georgetown University Medical Center.
This study is a continuation of work that led to a breakthrough in December 2011 when Schlegel and his colleagues demonstrated that he and his team had designed a laboratory technique that keep both normal as well as cancer cells alive indefinitely — which previously had not been possible.
They had discovered that adding two different substances to these cells (a Rho kinase inhibitor and fibroblast feeder cells) pushes them to morph into stem-like cells that stay alive indefinitely. When the two substances are withdrawn from the cells, they revert back to the type of cell that they once were. They dubbed these cells conditionally reprogrammed cells (CRCs).
Protein Test is First to Predict Rate of Progression in Lou Gehrig’s Disease
A novel test that measures proteins from nerve damage that are deposited in blood and spinal fluid reveals the rate of progression of amyotrophic lateral sclerosis (ALS) in patients, according to researchers from Mayo Clinic’s campus in Florida, Emory University and the University of Florida.
Their study, which appears online in the Journal of Neurology, Neurosurgery & Psychiatry, suggests this test, if perfected, could help physicians and researchers identify those patients at most risk for rapid progression. These patients could then be offered new therapies now being developed or tested.
ALS — also known as Lou Gehrig’s disease — is a progressive neurodegenerative disease caused by deterioration of motor neurons (nerve cells) that control voluntary muscle movement. The rate of progression varies widely among patients, and survival from the date of diagnosis can be months to 10 years or more, says Kevin Boylan, M.D., medical director of the ALS Clinic at Mayo Clinic in Florida.
"In the care of our ALS patients there is a need for more reliable ways to determine how fast the disease is progressing," says Dr. Boylan, who is the study’s lead investigator. "Many ALS researchers have been trying to develop a molecular biomarker test for nerve damage like this, and we are encouraged that this test shows such promise. Because blood samples are more readily collected than spinal fluid, we are especially interested in further evaluating this test in peripheral blood in comparison to spinal fluid."
There are no curative or even significantly beneficial therapies in clinics now for ALS treatment, but many are in development, Dr. Boylan says. A test like this could help identify those patients who are at risk for faster progression of weakness. With experimental treatments that primarily slow progression of ALS, detecting a treatment response in patients with faster progression may be easier to detect, says Dr. Boylan. Now, patients with varying rates of progression participate together in clinical studies, which can make analysis of a drug’s benefit difficult, he says.
"If there were a way to identify people who are likely to have relatively faster progression, it should be possible to conduct therapeutic trials with smaller numbers of patients in less time than is required presently," Dr. Boylan says.
A longer-range goal is to develop tests of this kind to gauge how well a patient is responding to experimental therapies, he adds.
The test measures neurofilament heavy form in blood and spinal fluid. These are proteins that provide structure to motor neurons, and when these nerves are damaged by the disease, the proteins break down and float free in blood serum and in the spinal fluid. Earlier research in this area was conducted by Gerry Shaw, Ph.D., a neuroscientist at the University of Florida, who is the study’s senior investigator and the developer of the neurofilament assay used in the study.
The researchers measured neurofilament heavy form in blood and spinal fluid samples from patients at Mayo Clinic and at Emory University, and correlated levels of the protein with rate of progression. “We demonstrated a solid association between higher levels of this protein and a faster progression of muscle weakness,” Dr. Boylan says. There was also evidence suggesting that ALS patients with higher protein levels may have shorter survival, he adds.
(Source: mayoclinic.org)
Scripps Research Institute Team Identifies a Potential Cause of Parkinson’s Disease that May Lead to New Treatment Options
Deciphering what causes the brain cell degeneration of Parkinson’s disease has remained a perplexing challenge for scientists. But a team led by scientists from The Scripps Research Institute (TSRI) has pinpointed a key factor controlling damage to brain cells in a mouse model of Parkinson’s disease. The discovery could lead to new targets for Parkinson’s that may be useful in preventing the actual condition.
The team, led by TSRI neuroscientist Bruno Conti, describes the work in a paper published online ahead of print on November 19, 2012 by the Journal of Immunology.
Parkinson’s disease plagues about one percent of people over 60 years old, as well as some younger patients. The disease is characterized by the loss of dopamine-producing neurons primarily in the substantia nigra pars compacta, a region of the brain regulating movements and coordination.
Among the known causes of Parkinson’s disease are several genes and some toxins. However, the majority of Parkinson’s disease cases remain of unknown origin, leading researchers to believe the disease may result from a combination of genetics and environmental factors.
Neuroinflammation and its mediators have recently been proposed to contribute to neuronal loss in Parkinson’s, but how these factors could preferentially damage dopaminergic neurons has remained unclear until now.