Neuroscience

Different anti-aging treatments work together and add years of life

The combination of two neuroprotective therapies, voluntary physical exercise, and the daily intake of melatonin has been shown to have a synergistic effect against brain deterioration in rodents with three different mutations of Alzheimer’s disease.

A study carried out by a group of researchers from the Barcelona Biomedical Research Institute (IIBB), in collaboration with the University of Granada and the Autonomous University of Barcelona, shows the combined effect of neuroprotective therapies against Alzheimer’s in mice.

Daily voluntary exercise and daily intake of melatonin, both of which are known for the effects they have in regulating circadian rhythm, show a synergistic effect against brain deterioration in the 3xTg-AD mouse, which has three mutations of Alzheimer’s disease.

"For years we have known that the combination of different anti-aging therapies such as physical exercise, a Mediterranean diet, and not smoking adds years to one’s life," Coral Sanfeliu, from the IIBB, explains to SINC. "Now it seems that melatonin, the sleep hormone, also has important anti-aging effects".

The experts analysed the combined effect of sport and melatonin in 3xTg-AD mice which were experiencing an initial phase of Alzheimer’s and presented learning difficulties and changes in behaviour such as anxiety and apathy.

The mice were divided into one control group and three other groups which would undergo different treatments: exercise –unrestricted use of a running wheel–, melatonin –a dose equivalent to 10 mg per kg of body weight–, and a combination of melatonin and voluntary physical exercise. In addition, a reference group of mice were included which presented no mutations of the disease.

"After six months, the state of the mice undergoing treatment was closer to that of the mice with no mutations than to their own initial pathological state. From this we can say that the disease has significantly regressed," Sanfeliu states.

The results, which were published in the journal Neurobiology of Aging, show a general improvement in behaviour, learning, and memory with the three treatments.

These procedures also protected the brain tissue from oxidative stress and provided good levels of protection from excesses of amyloid beta peptide and hyperphosphorylated TAU protein caused by the mutations. In the case of the mitochondria, the combined effect resulted in an increase in the analysed indicators of improved performance which were not observed independently.

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Mice with brittle skin, which tears off in order to escape predators, may offer clues to healing wounds without scarring, according to US researchers.

Some African spiny mice lost up to 60% of the skin from their backs, says the study published in the journal Nature. Unlike wounds in other mammals, the skin then rapidly healed and regrew hairs rather than forming a scar. Scientists want to figure out how the healing takes place and if it could apply to people.

Salamanders, some of which can regrow entire limbs, are famed for their regenerative abilities. It has made them the focus of many researchers hoping to figure out how to produce the same effect in people. Mammals, however, have very limited ability to regrow lost organs. Normally a scar forms to seal the wound. “This study shows that mammals as a group may in fact have higher regenerative abilities then they are given credit for,” said Dr Ashley Seifert from the University of Florida.

An evolutionary biologist at The University of Manchester, working with scientists in the United States, has found compelling evidence that parts of the brain can evolve independently from each other. It’s hoped the findings will significantly advance our understanding of the brain.

The unique 15-year study with researchers at the University of Tennessee and Harvard Medical School also identified several genetic loci that control the size of different brain parts.

The aim of the research was to find out if different parts of the brain can respond independently of each other to evolutionary stimulus (mosaic evolution) or whether the brain responds as a whole (concerted evolution). Unlike previous studies the researchers compared the brain measurements within just one species. The findings have been published in the journal Nature Communications.

The brains of approximately 10,000 mice were analysed. Seven individual parts of each brain were measured by volume and weight. The entire genome, except the Y chromosome, was scanned for each animal and the gene set for each brain part identified.

Dr Reinmar Hager from the Faculty of Life Sciences compared variation in the size of the brain parts to variation in the genes. He found that the variation in the size of brain parts is controlled by the specific gene set for that brain part and not a shared set of genes.

He also compared the measurements for each mouse to the overall size of its brain. Surprisingly he found very little correlation between the sizes of the brain parts and the overall size of the brain.

Dr Hager says: “If all the different brain parts evolved as a whole we would expect that the same set of genes influences size in all parts. However, we found many gene variations for each different part of the brain supporting a mosaic scenario of brain evolution. We also found very little correlation between the size of the brain parts and the overall size of the brain. This again supports the mosaic evolutionary hypothesis.”

Using the data collected from the mice Dr Hager and colleagues analysed the genes that influence the size of the brain to the genes that control the size of the body. They wanted to find out how independent size regulation of the brain is to that of the body.

They found evidence that the size of the brain is governed by an independent gene set to the one that controls the size of the body. Again they found vey little correlation between variations in the size of the body and the brain.

The evidence means that overall brain size can evolve independently of body size.

Following this research more work will be carried out to identify the specific genes that underlie the size of different parts in the brain

Dr Hager says: “If we can identify the specific genes that cause variations in the size of brain parts then there will be big implications for researchers looking at neuronal disease and brain development. We hope this research will significantly advance our understanding of the brain.”

Brain metastases are common secondary complications of other types of cancer, particularly lung, breast and skin cancer. The body’s own immune response in the brain is rendered powerless in the fight against these metastases by inflammatory reactions. Researchers at the MedUni Vienna have now, for the first time, precisely characterised the brain’s immune response to infiltrating metastases. This could pave the way to the development of new, less aggressive treatment options.

“The active phagocytes are quite literally overwhelmed by the tumour and even the white blood cells are too weak to fight off these metastases on their own; they have to be stimulated before they can have any effect,” explains oncologist Matthias Preusser from the University Department of Internal Medicine I and the Comprehensive Cancer Center (CCC), a joint institution operated by the MedUni Vienna and the Vienna General Hospital.

Brain tissue was obtained for investigation from autopsies carried out on people who had metastatic disease secondary to breast, lung or skin cancer. These are also the most common types of primary tumour. Brain metastases develop because they spread from the tumours into other parts of the body right up to the brain.

The scientists at the Clinical Institute of Neurology, the Centre for Brain Research, the CCC and the University Department of Internal Medicine I have discovered that metastases in the brain do encounter a wall of phagocytes, but it is too weak to successfully arrest the tumour’s development. To do this, white blood cells (lymphocytes) need to be mobilised in greater numbers as the second instance of the immune defence system.

These findings could lead to new therapeutic strategies being developed that will aim to increase the activation of white blood cells or other parts of the immune system – perhaps through medication such as antibody treatments or vaccines.

300 to 400 patients with brain metastases are treated each year at the MedUni Vienna. The standard treatment in most cases is radiotherapy to the head or generalised irradiation of the brain – which is associated with certain risks and possible side effects. Only in very few cases are drug-based treatment methods available for certain types of cancer. Says Preusser: “Our findings could represent an important step towards the development of less aggressive forms of treatment.”

The hippocampus represents an important brain structure for learning. Scientists at the Max Planck Institute of Psychiatry in Munich discovered how it filters electrical neuronal signals through an input and output control, thus regulating learning and memory processes. Accordingly, effective signal transmission needs so-called theta-frequency impulses of the cerebral cortex. With a frequency of three to eight hertz, these impulses generate waves of electrical activity that propagate through the hippocampus. Impulses of a different frequency evoke no transmission, or only a much weaker one. Moreover, signal transmission in other areas of the brain through long-term potentiation (LTP), which is essential for learning, occurs only when the activity waves take place for a certain while. The scientists even have an explanation for why we are mentally more productive after drinking a cup of coffee or in an acute stress situation: in their experiments, caffeine and the stress hormone corticosterone boosted the activity flow.

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UCI study points to role endocannabinoids play in common genetic cause of autism

American and European scientists have found that increasing natural marijuana-like chemicals in the brain can help correct behavioral issues related to fragile X syndrome, the most common known genetic cause of autism.

The work indicates potential treatments for anxiety and cognitive defects in people with this condition. Results appear online in Nature Communications.

Daniele Piomelli of UC Irvine and Olivier Manzoni of INSERM, the French national research agency, led the study, which identified compounds that inhibit enzymes blocking endocannabinoid transmitters called 2-AG in the striatum and cortex regions of the brain.

These transmitters allow for the efficient transport of electrical signals at synapses, structures through which information passes between neurons. In fragile X syndrome, regional synapse communication is severely limited, giving rise to certain cognitive and behavioral problems.

Fragile X syndrome is caused by a mutation of the FMR1 gene on the X chromosome. People born with it are mentally disabled; generally experience crawling, walking and language delays; tend to avoid eye contact; may be hyperactive or impulsive; and have such notable physical characteristics as an elongated face, flat feet and large ears.

The researchers stress that their findings, while promising, do not point to a cure for the condition.

“What we hope is to one day increase the ability of people with fragile X syndrome to socialize and engage in normal cognitive functions,” said Piomelli, a UCI professor of anatomy & neurobiology and the Louise Turner Arnold Chair in the Neurosciences.

The study involved mice genetically altered with FMR1 mutations that exhibited symptoms of fragile X syndrome. Treated with novel compounds that correct 2-AG protein signaling in brain cells, these mice showed dramatic behavioral improvements in maze tests measuring anxiety and open-space acceptance.

While other work has focused on pharmacological treatments for behavioral issues associated with fragile X syndrome, Piomelli noted that this is the first to identify the role endocannabinoids play in the neurobiology of the condition.

About endocannabinoids

Endocannabinoid compounds are created naturally in the body and share a similar chemical structure with THC, the primary psychoactive component of the marijuana plant, Cannabis. Endocannabinoids are distinctive because they link with protein molecule receptors — called cannabinoid receptors — on the surface of cells. For instance, when a person smokes marijuana, the cannabinoid THC activates these receptors. Because the body’s natural cannabinoids control a variety of factors — such as pain, mood and appetite — they’re attractive targets for drug discovery and development. Piomelli is one of the world’s leading endocannabinoid researchers. His groundbreaking work is showing that this system can be exploited by new treatments to combat anxiety, pain, depression and obesity.

Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinson’s disease, the progressive movement disorder. The discovery highlights potential new therapeutic targets for Parkinson’s and could lead to a blood test for the disease. The study, based mainly on analysis of human brain tissue, was published in the online edition of Nature Communications.

Studies of rare, familial (heritable) forms of Parkinson’s show that a protein called alpha-synuclein plays a role in the development of the disease.  People who have extra copies of the alpha-synuclein gene produce excess alpha-synuclein protein, which can damage neurons. The effect is most pronounced in dopamine neurons, a population of brain cells in the substantia nigra that plays a key role in controlling normal movement and is lost in Parkinson’s.  Another key feature of Parkinson’s is the presence of excess alpha-synuclein aggregates in the brain.

As the vast majority of patients with Parkinson’s do not carry rare familial mutations, a key question has been why these individuals with common sporadic Parkinson’s nonetheless acquire excess alpha-synuclein protein and lose critical dopamine neurons, leading to the disease.

Using a variety of techniques, including gene-expression analysis and gene-network mapping, the CUMC researchers discovered how common forms of alpha-synuclein contribute to sporadic Parkinson’s. “It turns out multiple different alpha-synuclein transcript forms are generated during the initial step in making the disease protein; our study implicates the longer transcript forms as the major culprits,” said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and neurology at CUMC. “Some very common genetic variants in the alpha-synuclein gene, present in many people, are known to impact the likelihood that an individual will suffer from sporadic Parkinson’s. In our study, we show that people with ‘bad’ variants of the gene make more of the elongated alpha-synuclein transcript forms. This ultimately means that more of the disease protein is made and may accumulate in the brain.”

“An unusual aspect of our study is that it is based largely on detailed analysis of actual patient tissue, rather than solely on animal models,” said Dr. Abeliovich. “In fact, the longer forms of alpha-synuclein are human-specific, as are the disease-associated genetic variants. Animal models don’t really get Parkinson’s, which underscores the importance of including the analysis of human brain tissue.”

“Furthermore, we found that exposure to toxins associated with Parkinson’s can increase the abundance of this longer transcript form of alpha-synuclein. Thus, this mechanism may represent a common pathway by which environmental and genetic factors impact the disease,” said Dr. Abeliovich.

The findings suggest that drugs that reduce the accumulation of elongated alpha-synuclein transcripts in the brain might have therapeutic value in the treatment of Parkinson’s. The CUMC team is currently searching for drug candidates and has identified several possibilities.

The study also found elevated levels of the alpha-synuclein elongated transcripts in the blood of a group of patients with sporadic Parkinson’s, compared with unaffected controls. This would suggest that a test for alpha-synuclein may serve as a biomarker for the disease. “There is a tremendous need for a biomarker for Parkinson’s, which now can be diagnosed only on the basis of clinical symptoms. The finding is particularly intriguing, but needs to be validated in additional patient groups,” said Dr. Abeliovich. A biomarker could also speed clinical trials by giving researchers a more timely measure of a drug’s effectiveness.

Most people equate “gray matter” with the brain and its higher functions, such as sensation and perception, but this is only one part of the anatomical puzzle inside our heads. Another cerebral component is the white matter, which makes up about half the brain by volume and serves as the communications network.

The gray matter, with its densely packed nerve cell bodies, does the thinking, the computing, the decision-making. But projecting from these cell bodies are the axons—the network cables. They constitute the white matter. Its color derives from myelin—a fat that wraps around the axons, acting like insulation.

Alex Schelgel, first author on a paper in the August 2012 Journal of Cognitive Neuroscience, has been using the white matter as a landscape on which to study brain function. An important result of the research is showing that you can indeed “teach old dogs new tricks.” The brain you have as an adult is not necessarily the brain you are always going to have. It can still change, even for the better.

"This work is contributing to a new understanding that the brain stays this plastic organ throughout your life, capable of change," Schlegel says. "Knowing what actually happens in the organization of the brain when you are learning has implications for the development of new models of learning as well as potential interventions in cases of stroke and brain damage."

Schlegel is a graduate student working under Peter Tse, an associate professor of psychological and brain sciences and a coauthor on the paper. “This study was Peter’s idea,” Schlegel says. “He wanted to know if we could see white matter change as a result of a long-term learning process. Chinese seemed to him like the most intensive learning experience he could think of.”

Twenty-seven Dartmouth students were enrolled in a nine-month Chinese language course between 2007 and 2009, enabling Schlegel to study their white matter in action. While many neuroscientists use magnetic resonance imaging (MRI) in brain studies, Schlegel turned to a new MRI technology, called diffusion tensor imaging (DTI). He used DTI to measure the diffusion of water in axons, tracking the communication pathways in the brain. Restrictions in this diffusion can indicate that more myelin has wrapped around an axon.

"An increase in myelination tells us that axons are being used more, transmitting messages between processing areas," Schlegel says. "It means there is an active process under way."

Their data suggest that white matter myelination is precisely what was seen among the language students. There is a structural change that goes along with this learning process. While some studies have shown that changes in white matter occurred with learning, these observations were made in simple skill learning and strictly on a “before and after” basis.

"This was the first study looking at a really complex, long-term learning process over time, actually looking at changes in individuals as they learn a task," says Schlegel. "You have a much stronger causal argument when you can do that."

The work demonstrates that significant changes are occurring in adults who are learning. The structure of their brains undergoes change.

"This flies in the face of all these traditional views that all structural development happens in infancy, early in childhood," Schlegel says. "Now that we actually do have tools to watch a brain change, we are discovering that in many cases the brain can be just as malleable as an adult as it is when you are a child or an adolescent."

NIH study of rats shows DNA regions thought inactive highly involved in body’s clock

Long stretches of DNA once considered inert dark matter appear to be uniquely active in a part of the brain known to control the body’s 24-hour cycle, according to researchers at the National Institutes of Health.

Working with material from rat brains, the researchers found some expanses of DNA contained the information that generate biologically active molecules. The levels of these molecules rose and fell, in synchrony with 24-hour cycles of light and darkness. Activity of some of the molecules peaked at night and diminished during the day, while the remainder peaked during the day and diminished during the night.

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Lithium is a ‘gold standard’ drug for treating bipolar disorder, however not everyone responds in the same way. New research published in BioMed Central’s open access journal Biology of Mood & Anxiety Disorders finds that this is true at the levels of gene activation, especially in the activation or repression of genes which alter the level the apoptosis (programmed cell death). Most notably BCL2, known to be important for the therapeutic effects of lithium, did not increase in non-responders. This can be tested in the blood of patients within four weeks of treatment.

A research team from Yale University School of Medicine measured the changing levels of gene activity in the blood of twenty depressed adult subjects with bipolar disorder before treatment, and then fortnightly once treatment with lithium carbonate had begun.

Over the eight weeks of treatment there were definite differences in the levels of gene expression between those who responded to lithium (measured using the Hamilton Depression Rating Scale) and those who failed to respond. Dr Robert Beech who led this study explained, “We found 127 genes that had different patterns of activity (turned up or down) and the most affected cellular signalling pathway was that controlled programmed cell death (apoptosis).”

For people who responded to lithium the genes which protect against apoptosis, including Bcl2 and IRS2, were up regulated, while those which promote apoptosis were down regulated, including BAD and BAK1.

The protein coded by BAK1 can open an anion channel in mitochondrial walls which leads to leakage of mitochondrial contents and activation of cell death pathways. Damage similar to this has been seen within the prefrontal cortex of the brain of patients with bipolar disorder. BAD protein is thought to promote BAK1 activity, while Bcl2 binds to BAK1 and prevents its ability to bind to the channel.

Dr Beech continued, “This positive swing in regulation of apoptosis for lithium responders was measurable as early as four weeks after the start of treatment, while in non-responders there was a measureable shift in the opposite direction. It seems then, that increased expression of BCL2 and related genes is  necessary for the therapeutic effects of lithium. Understanding these differences in genes expression may lead towards personalized treatment for bipolar disorder in the future.”

The real culprits of colour blindness are vision cells rather than unusual wiring in the eye and brain, recent research has shown.

The discovery brings scientists a step closer to restoring full colour vision for people who are colour blind – a condition that affects close to two million Australians, says Professor Paul Martin from The Vision Centre and The University of Sydney.

It may also help pave the way for an answer to one of the most common causes of blindness – age-related macular degeneration (AMD), which accounts for half of the legal blindness cases in Australia.

“There are millions of cones in our eyes – vision cells that pick up bright light and allow us to see colour,” Prof. Martin says. “They are nicknamed red, green and blue cones because they are sensitive to different wavelengths of light.

“We now know that in the macular region of the eye, each cone has its own ’private line’ into the optic nerve and the brain. Just as a painter can mix from three tubes of paint to produce a wide and vivid palette, our brain uses the ‘private lines’ from the three cone types to create thousands of colour sensations.

Scientists previously thought that full colour vision depends on specialised nerve wiring in the eye and brain, but animal studies show that the wiring is identical for monkeys whether they have normal or abnormal colour vision, Prof. Martin says.

“This tells us that there’s nothing wrong in the brain – it’s only working with the signals that it receives on the ‘private lines’,” he says. “So the only difference in normal and abnormal colour vision is caused by the first stage of sight, which points to faulty cones. Either they have failed to develop, or else they are picking up abnormal wavelengths.

“Now that we know faulty wiring isn’t the cause, we can concentrate on fixing the cones, which are controlled by genes – and thus prone to mutation or mistakes during cell replication. There are already promising results from gene therapy as a way to restore full colour vision in colour blind monkeys.”

“While we have still have some way to go, the benefits of this gene therapy – if successful – can potentially extend beyond providing complete colour vision,” he says.

“If we can get these genes to work in human eyes, it means that the same approach might be possible for other visual problems – including blinding diseases such as macular degeneration.”

"In macular degeneration, energy supplies to the macula can’t keep up with demand. So the ‘private line’ system must be very energy-intensive. Gene therapy could be used to turn down the cones’ energy demand, or to increase energy supply from supporting cells to cone cells,” Prof. Martin says.

“Together with clinical researchers at the Save Sight Institute, we are now working hard to find out exactly how many ‘private lines’ there are in humans. That can point us to where energy demand is highest and we can target gene therapy to the right place.

"So animal research on ‘private lines’ for colour vision has given new clues for understanding one of the most important visual diseases – macular degeneration – in humans."