The 'Big Bang' of Alzheimer's: Scientists ID genesis of disease

Scientists have discovered a "Big Bang" of Alzheimer's disease -- the precise point at which a healthy protein becomes toxic but has not yet formed deadly tangles in the brain.

A study from UT Southwestern's O'Donnell Brain Institute provides novel insight into the shape-shifting nature of a tau molecule just before it begins sticking to itself to form larger aggregates. The revelation offers a new strategy to detect the devastating disease before it takes hold and has spawned an effort to develop treatments that stabilize tau proteins before they shift shape.

"We think of this as the Big Bang of tau pathology. This is a way of peering to the very beginning of the disease process."

Dr. Mark Diamond, Director for UT Southwestern's Center for Alzheimer's and Neurodegenerative Diseases "This is perhaps the biggest finding we have made to date, though it will likely be some time before any benefits materialize in the clinic. This changes much of how we think about the problem," said Dr. Marc Diamond, Director for UT Southwestern's Center for Alzheimer's and Neurodegenerative Diseases and a leading dementia expert credited with determining that tau acts like a prion -- an infectious protein that can self-replicate.

The study published in eLife contradicts the previous belief that an isolated tau protein has no distinct shape and is only harmful after it begins to assemble with other tau proteins to form the distinct tangles seen in the brains of Alzheimer's patients.

Scientists made the discovery after extracting tau proteins from human brains and isolating them as single molecules. They found that the harmful form of tau exposes a part of itself that is normally folded inside. This exposed portion causes it to stick to other tau proteins, enabling the formation of tangles that kill neurons.

"We think of this as the Big Bang of tau pathology," said Dr. Diamond, referring to the prevailing scientific theory about the formation of the universe. "This is a way of peering to the very beginning of the disease process. It moves us backward to a very discreet point where we see the appearance of the first molecular change that leads to neurodegeneration in Alzheimer's. This work relied on a close collaboration with my colleague, Dr. Lukasz Joachimiak."

Despite billions of dollars spent on clinical trials through the decades, Alzheimer's disease remains one of the most devastating and baffling diseases in the world, affecting more than 5 million Americans alone.

Dr. Diamond is hopeful the scientific field has turned a corner, noting that identifying the genesis of the disease provides scientists a vital target in diagnosing the condition at its earliest stage, before the symptoms of memory loss and cognitive decline become apparent.

His team's next steps are to develop a simple clinical test that examines a patient's blood or spinal fluid to detect the first biological signs of the abnormal tau protein. But just as important, Dr. Diamond said, efforts are underway to develop a treatment that would make the diagnosis actionable.

He cites a compelling reason for cautious optimism: Tafamidis, a recently approved drug, stabilizes a different shape-shifting protein called transthyretin that causes deadly protein accumulation in the heart, similar to how tau overwhelms the brain.

"The hunt is on to build on this finding and make a treatment that blocks the neurodegeneration process where it begins," Dr. Diamond said. "If it works, the incidence of Alzheimer's disease could be substantially reduced. That would be amazing."

Dr. Diamond's lab, at the forefront of many notable findings relating to tau, previously determined that tau acts like a prion -- an infectious protein that can spread like a virus through the brain. The lab has determined that tau protein in the human brain can form many distinct strains, or self-replicating structures, and developed methods to reproduce them in the laboratory. He said his newest research indicates that a single pathological form of tau protein may have multiple possible shapes, each associated with a different form of dementia.

Dr. Diamond, who holds the Distinguished Chair in Basic Brain Injury and Repair, is founding Director of the Center for Alzheimer's and Neurodegenerative Diseases, and Professor of Neurology & Neurotherapeutics with the Peter O'Donnell Jr. Brain Institute at UT Southwestern. He collaborated on the study with co-corresponding author Dr. Joachimiak, an Assistant Professor in the Center for Alzheimer's and Neurodegenerative Diseases and an Effie Marie Cain Scholar in Medical Research.

The research was supported with funding from the Rainwater Charitable Foundation, the National Institutes of Health, and the Effie Marie Cain Endowed Scholarship.

Musical surgery: Flutist plays Bach & Mozart as doctors cut out her brain tumor

Surgery to remove a brain tumor is terrifying at best, but one patient decided to make the process a little more bearable, by playing the flute during the operation, providing surgeons with a recital in the most unusual of places.

Sofia Pinaeva, 28, underwent the surgery at University Hospital in Graz, Austria. She opted to stay awake for the surgery; if asleep, the patient runs a higher risk of losing brain function in the procedure.

But staying awake is one thing. Playing the flute while surgeons slice into your brain is another.

“From the outside, that's rather unusual,” 28-year-old Pinaeva said, while laughing, as reported by Kurier. However, the music teacher said there was “no question” about whether she would perform during the operation.

 

FILE PHOTO © Sam Edwards

“Bach, Mozart, I played everything that came to mind,” she said.

While it seems crazy, her surgeons would have had to make sure that Pinaeva’s mind was active and cognizant in another way, had she not chosen to play the flute.

“We are looking for tasks and functions that are easy to answer during the operation,” psychologist Karla Zaar said. “That would be different for every patient. Some have to describe pictures in a whole sentence, for example: 'This is a tree.'” The clinic has also had patients who identified dinosaurs from photos or who completed mathematical equations during such procedures.

Pinaeva is now recovering from her operation, which removed about half of the tumor – more than would have been possible were she to have slept during the surgery. She is doing well, and even arranged a garden party with friends just days after the surgery.

“I have a brain tumor,” she said. “Some people react as if I'm already dead. But it goes on. It is important to me to show that this diagnosis is not a death sentence.”

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Fountain of youth? Scientists pinpoint gene related to aging

There may have been a major scientific breakthrough in understanding aging, as scientists have identified a gene that plays a key role in kick-starting the process that makes cells start turning "old."

Researchers from the University of Buffalo in New York have discovered that one particular gene, CD36, triggers the beginning of the phenomenon of senescence. After it is activated, cells stop dividing and start to wither.

Senescence is a natural occurrence in the life cycle of every cell. It has long been the focus of medical research, because senescent cells are thought to contribute to a range of ailments, from heart disease and cataracts to arthritis.

 
© Getty

The new study, published in the journal Molecular Omics, found that CD36 was particularly active in older, senescent cells. The scientists were also able to cause young, healthy cells to quickly act as if they were old by increasing their CD36 activity.

“What we found was very surprising,” one of the researchers, Ekin Atilla-Gokcumen, explained. “Senescence is a very complex process, and we didn’t expect that altering expression of one gene could spark it, or cause the same effect in surrounding cells.”

The researchers did not set out to investigate CD36. Rather, they wanted to catalogue all genes related to the aging of cells. They were particularly interested in the lipid-related genes that are involved in this process, because previous studies have shown that lipids play an important role in cellular aging.

CD36 quickly emerged as a gene of interest because it repeatedly popped up in different tests designed to capture the factors that cause cell aging.

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While the discovery is exciting, the gene’s exact role in the aging process remains shrouded in mystery. Scientists know that CD36 guides the body in building a protein that sits on the surface of cells, but what exactly the protein does is still being studied. The researchers say the gene represents an exciting topic for deeper research into how cells age.

“Our research identifies CD36 as a candidate for further study. Senescence is a fundamental aspect of being a cell, but there is still a lot that we don’t know about it,” said Omer Gokcumen, one of the paper’s authors. “Senescence seems to have implications for old age and cancer, so understanding it is very important.”

Are humans causing cancer in wild animals?

As humans, we know that some of our activities can cause cancer to develop in our bodies. Smoking, poor diets, pollution, chemicals used as additives in food and personal hygiene products, and even too much sun are some of the things that contribute to an increased risk of cancer.

But, are human activities also causing cancer in wild animals? Are we oncogenic -- a species that causes cancer in other species?

Researchers from Arizona State University's School of Life Sciences think so and are urgently calling for research into this topic. In a paper published online today in "Nature Ecology & Evolution," Mathieu Giraudeau and Tuul Sepp, both postdoctoral researchers in the lab of ASU life sciences professor Kevin McGraw, say that humans are changing the environment in a way that causes cancer in wild animal populations.

"We know that some viruses can cause cancer in humans by changing the environment that they live in -- in their case, human cells -- to make it more suitable for themselves," said Sepp. "Basically, we are doing the same thing. We are changing the environment to be more suitable for ourselves, while these changes are having a negative impact on many species on many different levels, including the probability of developing cancer."

In the paper, Giraudeau and Sepp and a team of international researchers, point out many pathways and previous scientific studies that show where human activities are already taking a toll on animals. These include chemical and physical pollution in our oceans and waterways, accidental release of radiation into the atmosphere from nuclear plants, and the accumulation of microplastics in both land- and water-based environments. In addition, exposure to pesticides and herbicides on farmlands, artificial light pollution, loss of genetic diversity and animals eating human food are known to cause health problems.

"Cancer in wild populations is a completely ignored topic and we wanted to stimulate research on this question," shared Giraudeau. "We recently published several theoretical papers on this topic, but this time, we wanted to highlight the fact that our species can strongly influence the prevalence of cancer in many other species of our planet.

"Cancer has been found in all species where scientists have looked for it and human activities are known to strongly influence cancer rate in humans. So, this human impact on wild environments might strongly influence the prevalence of cancer in wild populations with additional consequences on ecosystem functioning," he said.

Even something such as artificial light and light pollution, as well as food meant for humans, are negatively affecting wild animals.

Sepp said: "It is already known in human studies that obesity and nutrient deficiency can cause cancer, but these issues have been mostly overlooked in wild animals. At the same time, more and more wild species are in contact with anthropogenic food sources. In humans, it's also known that light at night can cause hormonal changes and lead to cancer. Wild animals living close to cities and roads face the same problem -- there is no darkness anymore. For example, in birds, their hormones -- the same that are linked to cancer in humans -- are affected by light at night. So, the next step would be to study if it also affects their probability of developing tumors."

While these scientists are urgently calling for studies on cancer and its causes in wild animal populations, they realize that this is no easy subject to study.

"The next step is definitely to go into the field and measure cancer rate in wild populations," said Giraudeau. "We are now trying to develop some biomarkers to be able to study this. I think it would be interesting to measure cancer prevalence in wild animals in human-impacted environments and also in more preserved areas for the same species."

If humans are the cause of cancer in wild animals, then many species may be more threatened than people realize. Yet Tuul said, there is reason to hold out hope.

"To me, the saddest thing is that we already know what to do. We should not destroy the habitats of wild animals, pollute the environment, and feed wild animals human food," shared Sepp. "The fact that everybody already knows what to do, but we are not doing it, makes it seem even more hopeless.

"But I see hope in education. Our kids are learning a lot more about conservation issues than our parents did. So, there is hope that the decision-makers of the future will be more mindful of the anthropogenic effects on the environment."

Scientists discover new way that HIV evades the immune system

Scientists have just discovered a new mechanism by which HIV evades the immune system, and which shows precisely how the virus avoids elimination. The new research shows that HIV targets and disables a pathway involving a number of biological molecules that are key in blocking viral activity and clearing infection.

HIV remains a major global health problem, with over 40 million people infected worldwide. And while people living with HIV have been treated with anti-retroviral therapy for over 30 years, this favoured therapeutic option merely prevents the progression of the disease to AIDS - it doesn't cure patients of HIV.

The discovery, which opens the door to a new era of HIV research focused on curing people living with the , has just been published in international journal, EBioMedicine, which is a collaborative online journal from Cell Press and the Lancet.

During any viral our immune system produces a powerful molecule (Interferon), which 'interferes' with the infection and the replication of viruses. Interferon activates an assembly line of molecules in our cells—via the Interferon signalling pathway - which causes the body to make antivirals that help to clear the infection.

However, when patients are being treated with anti-retroviral therapy, HIV is not fully cleared by our immune system. Therefore, the scientists from Trinity College Dublin behind the research investigated whether HIV was somehow blocking the Interferon signalling pathway and thus avoiding the immune response that is designed to cure viral infection. The findings confirmed their suspicions.

Assistant Professor in Immunology at Trinity, Nigel Stevenson, led the work. He said: "We discovered that HIV promotes the destruction of the anti-viral Interferon signalling pathway. Essentially, HIV uses the machinery in our own cells to do this, and the virus is thus able to reduce the production of many important anti-viral molecules. Without these anti-viral , our immune system can't clear ."

"Our new revelation sheds new light on how HIV avoids elimination, which, in turn, may explain why HIV is still not a curable disease. We feel this discovery could mark a paradigm shift in our understanding of how this virus evades our . It should open the door to a new era of HIV research aiming to cure and eradicate this deadly virus."

Coming soon: Male contraceptive pill inches closer

Researchers are one step closer to developing a male contraceptive pill, a medical conference has heard. Early trials show the pill to be both safe and effective.

The study, led by Professor Stephanie Page of the University of Washington, included 100 men aged between 18 and 50. The men were split into groups of between 17-20 and given three different doses of pills known as dimethandrolone undecanoate, or DMAU. Out of each group, five subjects were given a placebo while another 12-15 were given daily doses of DMAU for 28 days. Some 83 men completed the study.

READ MORE: ‘One size does not fit all’: Chinese condoms are too small for Zimbabweans, says health minister

The highest dose, 400mg of DMAU, showed “marked suppression” of testosterone levels as well as two other hormones required for the production of sperm. The results were compared to longer-term studies and appeared consistent with effective male contraception.

@RTUKnews Teach kids how to get pregnant, UK doctors say https://trib.al/Ml0P6ax
 

"DMAU is a major step forward in the development of a once-daily 'male pill,'" Page reportedly told the Endocrine Society’s 100th annual meeting in Chicago. "Many men say they would prefer a daily pill as a reversible contraceptive, rather than long-acting injections or topical gels, which are also in development."

Page also said that few participants in the study reported having symptoms consistent with testosterone deficiency, although all groups reported weight gain and decreases in healthy cholesterol. "These promising results are unprecedented in the development of a prototype male pill," Page said. "Longer term studies are currently underway to confirm that DMAU taken every day blocks sperm production."

@RT_com Condom-free male contraceptive successfully trialed on monkeys - next stop, human testing https://on.rt.com/82jm

Various male contraceptives have been trialed in the past. In February last year, a gel injection used to block the sperm-carrying tubes, known as vas deferens, was trialed on monkeys. The Vasalgel injection, made by the Parsemus Foundation, has gone forward for human trials.

Brain is less flexible than we thought when learning

Nobody really knows how the activity in your brain reorganizes as you learn new tasks, but new research reveals that the brain has various mechanisms and constraints by which it reorganizes its neural activity when learning over the course of a few hours. The new research finds that, when learning a new task, the brain is less flexible than previously thought.

The research, published today in Nature Neuroscience, examined the changes that take place in the brain when learning a new task. To truly see how neural activity changes during learning, we need to look bigger -- at populations of neurons, rather than one neuron at a time, which has been the standard approach to date.

The research team used a brain-computer interface (BCI), where subjects move a cursor on a computer screen by thought alone. As with learning to play a new sport, they found that subjects learned to control the cursor more accurately with practice. They then investigated how the activity in the brain changed during learning that enabled the improved performance. They found that, on a time scale of a few hours, the brain does not reconfigure its neural activity to maximize the speed and accuracy by which it moves the cursor.

"In this experimental paradigm, we're able to track all of the neurons that can lead to behavioral improvements and look at how they all change simultaneously," says Steve Chase, an associate professor of biomedical engineering at Carnegie Mellon and the Center for the Neural Basis of Cognition. "When we do that, what we see is a really constrained set of changes that happen, and it leads to this suboptimal improvement of performance. And so, that implies that there are limits that constrain how flexible your brain is, at least on these short time scales."

When we're learning a new task, we can't instantaneously learn it to proficiency, in part due to the way in which the neurons are wired up in the brain. Learning takes time, and there are mechanisms by which neurons can change the way they communicate with each other to enable learning -- some of which can be fast, and some of which can take longer. The team found that the brain operates under a more stringent set of constraints than originally thought, resulting in good learning on the short term, but nevertheless suboptimal performance in controlling the BCI cursor.

Imagine a tennis player whose friends have asked her to play squash. When she picks up the squash racket, it's lighter than the tennis racket she is used to, and it has a slightly different balance point. But since she's a good tennis player, this difference in rackets doesn't cause her to miss the ball completely. She adjusts quickly, but she hasn't immediately picked up the swing form of a squash player. To really become an expert, it will require a long period of training with the new equipment. However, her experienced squash-playing friends will quickly see that she is a tennis player, because until she's learned the proper technique, she'll be swinging the squash racket the same as she would a tennis racket.

"Just as it takes time to train a person to swing a squash racket like an expert, it takes time to train one's neurons to produce the ideal activity patterns," says Byron Yu, associate professor of biomedical engineering and electrical and computer engineering at Carnegie Mellon. "When faced with a new task, we're finding that the brain is constrained to take the neural activity patterns that it's capable of generating right now and use them as effectively as possible in this new task."

"When we learn, at first the brain tends to not produce new activity patterns, but to repurpose the activity patterns it already knows how to generate," says Aaron Batista, an associate professor in the Department of Bioengineering at the University of Pittsburgh. "Learning over the course of a few hours is suboptimal. When first learning something new, our brain doesn't seem to be able to change its activity in the best possible way to allow us to be proficient at new skills.."

Acquiring a skill is very difficult, and it takes a lot of time and a lot of practice. But when you're first starting to learn a new skill, your brain has to adjust quickly to the new task. The researchers found that the brain is constrained to take neural activity patterns it already knows and use them for the new task. By repurposing neuron patterns the brain is already capable of generating, the brain applies a "quick and dirty fix" to the new problem it's facing.

"None of us predicted this outcome," says Matthew Golub, a postdoctoral researcher in electrical and computer engineering at Carnegie Mellon. "Learning is far more limited on the scale of a few hours than any of us were expecting when we started this. We were all surprised that the brain wasn't able to choose the best strategy possible."

The research was done in collaboration with the Center for Neural Basis of Cognition, a cross-university research and educational program between Carnegie Mellon and the University of Pittsburgh that leverages each institution's strengths to investigate the cognitive and neural mechanisms that give rise to biological intelligence and behavior.

Air pollutants linked to abnormal fetal growth

The findings, published in the International Journal of Epidemiology, were based on data collected from more than 8,000 women in Lanzhou, China from 2010 to 2012.

The researchers said that, to their knowledge, it is the first study of its kind to be conducted in areas with very high .

"There is a lack of studies investigating the association between air and fetal overgrowth," said Yawei Zhang, M.D., associate professor at YSPH. "We analyzed data from Lanzhou Birth Cohort Study to investigate the hypothesis that exposure to high levels of PM10 during pregnancy increases the risk of abnormal fetal growth, including both undergrowth and overgrowth, to determine if and how expectant mothers could protect themselves from possible contributing pollutants."

In collaboration with researchers from the Gansu Provincial Maternity and Child Care Hospital, the Yale scientists collected the daily average concentration for PM10—a diverse class of air pollution with health implications—from the government monitoring stations in Lanzhou. Using ultrasound measures of four fetal growth parameters during pregnancy, the researchers examined the associations between PM10 exposure and risk of abnormal fetal growth.

The researchers consistently identified positive associations between higher levels of exposure to a mixture of pollutants from car fumes, industry emissions, or construction activities and fetal head circumference overgrowth, they said.

Pregnant women's home and work addresses were collected through in-person interviews, and researchers calculated daily PM10 concentrations by incorporating each participant's home and work addresses.

Zhang says the novel finding that high levels of PM10 are associated with risk of overgrowth should be confirmed by other studies in different populations, and that it is also important to identify the specific pollutants that are responsible for this association by investigating the components of PM10.

"Our results have important public health implications and call for future studies to explore the underlying mechanisms and postnatal consequences to the findings," says Zhang. "We are going to replicate the findings in another and will continue to identify individuals who are more susceptible to air pollution."

Women in the region may lower the risk of fetal overgrowth by choosing their inception time and reducing their outdoor activities during the days with high , said Zhang.

Pregnant women who came to the Gansu Provincial Maternity and Child Care Hospital for delivery in 2010-2012 and who were 18 years or older with gestation age of more than 20 weeks were eligible to participate in this study.

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