New Research on Walnuts and the Fight Against Alzheimer’s Disease

A new animal study published in the Journal of Alzheimer’s Disease indicates that a diet including walnuts may have a beneficial effect in reducing the risk, delaying the onset, slowing the progression of, or preventing Alzheimer’s disease.

Research led by Abha Chauhan, PhD, head of the Developmental Neuroscience Laboratory at the New York State Institute for Basic Research in Developmental Disabilities (IBR), found significant improvement in learning skills, memory, reducing anxiety, and motor development in mice fed a walnut-enriched diet.

The researchers suggest that the high antioxidant content of walnuts (3.7 mmol/ounce) may have been a contributing factor in protecting the mouse brain from the degeneration typically seen in Alzheimer’s disease. Oxidative stress and inflammation are prominent features in this disease, which affects more than five million Americans.

“These findings are very promising and help lay the groundwork for future human studies on walnuts and Alzheimer’s disease – a disease for which there is no known cure,” said lead researcher Dr. Abha Chauhan, PhD. “Our study adds to the growing body of research that demonstrates the protective effects of walnuts on cognitive functioning.”

The research group examined the effects of dietary supplementation on mice with 6 percent or 9 percent walnuts, which are equivalent to 1 ounce and 1.5 ounces per day, respectively, of walnuts in humans. This research stemmed from a previous cell culture study led by Dr. Chauhan that highlighted the protective effects of walnut extract against the oxidative damage caused by amyloid beta protein. This protein is the major component of amyloid plaques that form in the brains of those with Alzheimer’s disease.

Someone in the United States develops Alzheimer’s disease every 67 seconds, and the number of Americans with Alzheimer’s disease and other dementias are expected to rapidly escalate in coming years as the baby boom generation ages. By 2050, the number of people age 65 and older with Alzheimer’s disease may nearly triple, from five million to as many as 16 million, emphasizing the importance of determining ways to prevent, slow or stop the disease. Estimated total payments in 2014 for all individuals with Alzheimer’s disease and other dementias are $214 billion.

Walnuts have other nutritional benefits as they contain numerous vitamins and minerals and are the only nut that contains a significant source of alpha-linolenic acid (ALA) (2.5 grams per ounce), an omega-3 fatty acid with heart and brain-health benefits. The researchers also suggest that ALA may have played a role in improving the behavioral symptoms seen in the study.

Male and female brains aren’t equal when it comes to fat

Researchers have found that male and female brains respond in remarkably different ways to high-fat meals. Those differences in the brain lead to greater inflammation and increased health risks in males that indulge on fatty foods in comparison to females, a new study in mice shows. The findings reported in the Cell Press journal Cell Reports on October 16th may help to explain observed differences in obesity outcomes between women and men – premenopausal women carrying extra weight fare better than men do – and suggest that dietary advice should be made more sex-specific.

"Our findings, for the first time, suggest that males and females respond to high-fat diets differently," said Deborah Clegg of the Cedar-Sinai Diabetes And Obesity Research Institute in Los Angeles. "The data would suggest that is probably ‘ok’ for females to occasionally have a high-fat meal, where it is not recommended for males.

"The way we treat patients and provide dietary and nutritional advice should be altered. We might be less concerned about an occasional hamburger for women, but for men, we might more strongly encourage avoidance, especially if they have pre-existing diseases such as heart disease or type 2 diabetes."

Earlier data from Clegg’s team and others had suggested that inflammation in the brain is tied to overeating, blood sugar imbalances, and increased inflammation in other parts of the body, including fat tissue. Those effects can be triggered, in males in particular, by short-term exposure to a high-fat diet.

The researchers say they were initially shocked to discover that male and female brains differ in their fatty acid composition. When they manipulated male mouse brains to have the fatty acid profile of females, they found that those animals were protected from the ill effects of a diet high in fat.

When males with average male brains entered an inflammatory state after eating diets high in fat, they also suffered from reduced cardiac function in a way that female animals in the study did not. Those sex differences in the brain’s response to fat are related to differences between females and males in estrogen and estrogen receptor status.

Clegg says her team is now working out a strategy to confirm whether the findings in mice apply to people too. If they do, there will be some very immediate practical implications for what men and women should put on their plates.

"We have always had ‘one size fits all’ with respect to our nutritional information and our pharmaceutical approach," Clegg said. "Our data begin to suggest that sex should be factored in, and men should be more closely monitored for fat intake and inflammation than women."

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Study finds link between neural stem cell overgrowth and autism-like behavior in mice

People with autism spectrum disorder often experience a period of accelerated brain growth after birth. No one knows why, or whether the change is linked to any specific behavioral changes.

A new study by UCLA researchers demonstrates how, in pregnant mice, inflammation, a first line defense of the immune system, can trigger an excessive division of neural stem cells that can cause “overgrowth” in the offspring’s brain.

The paper appears Oct. 9 in the online edition of the journal Stem Cell Reports. 

“We have now shown that one way maternal inflammation could result in larger brains and, ultimately, autistic behavior, is through the activation of the neural stem cells that reside in the brain of all developing and adult mammals,” said Dr. Harley Kornblum, the paper’s senior author and a director of the Neural Stem Cell Research Center at UCLA’s Semel Institute for Neuroscience and Human Behavior.

In the study, the researchers mimicked environmental factors that could activate the immune system — such as an infection or an autoimmune disorder — by injecting a pregnant mouse with a very low dose of lipopolysaccharide, a toxin found in E. coli bacteria. The researchers discovered the toxin caused an excessive production of neural stem cells and enlarged the offspring’s’ brains.

Neural stem cells become the major types of cells in the brain, including the neurons that process and transmit information and the glial cells that support and protect them.

Notably, the researchers found that mice with enlarged brains also displayed behaviors like those associated with autism in humans. For example, they were less likely to vocalize when they were separated from their mother as pups, were less likely to show interest in interacting with other mice, showed increased levels of anxiety and were more likely to engage in repetitive behaviors like excessive grooming.

Kornblum, who also is a professor of psychiatry, pharmacology and pediatrics at the David Geffen School of Medicine at UCLA, said there are many environmental factors that can activate a pregnant woman’s immune system.

“Although it’s known that maternal inflammation is a risk factor for some neurodevelopmental disorders such as autism, it’s not thought to directly cause them,” he said. He noted that autism is clearly a highly heritable disorder, but other, non-genetic factors clearly play a role.

The researchers also found evidence that the brain growth triggered by the immune reaction was even greater in mice with a specific genetic mutation — a lack of one copy of a tumor suppressor gene called phosphatase and tensin homolog, or PTEN. The PTEN protein normally helps prevent cells from growing and dividing too rapidly. In humans, having an abnormal version of the PTEN gene leads to very large head size or macrocephaly, a condition that also is associated with a high risk for autism.

“Autism is a complex group of disorders, with a variety of causes,” Kornblum said. “Our study shows a potential way that maternal inflammation could be one of those contributing factors, even if it is not solely responsible, through interactions with known risk factors.”

In addition, the team found that the proliferation of neural stem cell and brain overgrowth was stimulated by the activation of a specific molecular pathway. (A pathway is a series of actions among molecules within a cell that leads to a certain cell function.) This pathway involved the enzyme NADPH oxidase, which the UCLA researchers have previously found to be associated with neural stem cell growth.

“The discovery of these mechanisms has identified new therapeutic targets for common autism-associated risk factors,” said Janel Le Belle, an associate researcher in Kornblum’s lab and the paper’s lead author. “The molecular pathways that are involved in these processes are ones that can be manipulated and possibly even reversed pharmacologically.

“In agreement with past clinical findings, these data add to the significant evidence that autism-associated brain alterations begin prenatally and continue to evolve after birth,” she said.

Kornblum added that the findings that neural stem cell hyper-proliferation can contribute to autism-associated features may be somewhat surprising. “Autism neuropathology is primarily thought of as a dysregulation of neuronal connectivity, although the molecular and cellular means by which this occurs is not known,” he said. “Therefore, our hypothesis — that one potential means by which autism may develop is through an overproduction of cells in the brain, which then results in altered connectivity — is a new way of thinking about autism etiology.”

The next step, the researchers say, is to determine if and how the changes they observed lead to changes in the connections between brain cells, and if those effects can be altered after they have happened.

Blood test may help determine who is at risk for psychosis

A study led by University of North Carolina at Chapel Hill researchers represents an important step forward in the accurate diagnosis of people who are experiencing the earliest stages of psychosis.

Psychosis includes hallucinations or delusions that define the development of severe mental disorders such as schizophrenia. Schizophrenia emerges in late adolescence and early adulthood and affects about 1 in every 100 people. In severe cases, the impact on a young person can be a life compromised, and the burden on family members can be almost as severe.

The study published in the journal Schizophrenia Bulletin reports preliminary results showing that a blood test, when used in psychiatric patients experiencing symptoms that are considered to be indicators of a high risk for psychosis, identifies those who later went on to develop psychosis.

“The blood test included a selection of 15 measures of immune and hormonal system imbalances as well as evidence of oxidative stress,” said Diana O. Perkins, MD, MPH, professor of psychiatry in the UNC School of Medicine and corresponding author of the study. She is also medical director of UNC’s Outreach and Support Intervention Services (OASIS) program for schizophrenia.

“While further research is required before this blood test could be clinically available, these results provide evidence regarding the fundamental nature of schizophrenia, and point towards novel pathways that could be targets for preventative interventions,” Perkins said.

Clark D. Jeffries, PhD, bioinformatics scientist at the UNC-based Renaissance Computing Institute (RENCI), is a co-author of the study, which was conducted as part of the North American Prodrome Longitudinal Study (NAPLS), an international effort to understand risk factors and mechanisms for development of psychotic disorders. 

“Modern, computer-based methods can readily discover seemingly clear patterns from nonsensical data,” said Jeffries. “Added to that, scientific results from studies of complex disorders like schizophrenia can be confounded by many hidden dependencies. Thus, stringent testing is necessary to build a useful classifier. We did that.”

The study concludes that the multiplex blood assay, if independently replicated and if integrated with studies of other classes of biomarkers, has the potential to be of high value in the clinical setting.

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Researchers discover fever’s origin

Fever is a response to inflammation, and is triggered by an onset of the signaling substance prostaglandin. Researchers at Linköping University can now see precisely where these substances are produced – a discovery that paves the way for smarter drugs.

When you take an aspirin, all production of prostaglandins in the body is suppressed. All symptoms of inflammation are eased simultaneously, including fever, pain and loss of appetite. But it might not always be desirable to get rid of all symptoms – there is a reason why they appear.

”Perhaps you want to inhibit loss of appetite but retain fever. In the case of serious infections, fever can be a good thing,” says David Engblom, senior lecturer in neurobiology at Linköping University.

Eleven years ago he had his first breakthrough as a researcher when he uncovered the mechanism behind the formation of prostaglandin E₂ during fever. These signaling molecules cannot pass the blood-brain barrier, the purpose of which is to protect the brain from hazardous substances. Engblom showed that instead, they could be synthesised from two enzymes in the blood vessels on the inside of the brain, before moving to the hypothalamus, where the body’s thermostat is located.

Previous work from the research team described a very simple mechanism, but there was not yet proof that it was important in real life. The study to be published in The Journal of Neuroscience with David Engblom and his doctoral student Daniel Wilhelms as lead authors is based on tests with mice that lack the enzymes COX-2 and mPGES-1 in the brain’s blood vessels. When they were infected with bacterial toxins the fever did not appear, while other signs of inflammation were not affected.

”This shows that those prostaglandins which cause fever are formed in the blood-brain barrier – nowhere else. Now it will be interesting to investigate the other inflammation symptoms. Knowledge of this type can be useful when developing drugs that ease certain symptoms, but not all of them,” explains David Engblom.

For many years there has been debate as to where the fever signaling originates. Three alternative ideas have been proposed. Firstly, that it comes from prostaglandins circulating in the blood, secondly that it comes from immune cells in the brain, and thirdly Engblom’s theory, which stresses the importance of the brain’s blood vessels. The third proposal can now be considered confirmed.

Research underway to create pomegranate drug to stem Alzheimer’s and Parkinson’s

The onset of Alzheimer’s disease can be slowed and some of its symptoms curbed by a natural compound that is found in pomegranate. Also, the painful inflammation that accompanies illnesses such as rheumatoid arthritis and Parkinson’s disease could be reduced, according to the findings of a two-year project headed by University of Huddersfield scientist Dr Olumayokun Olajide, who specialises in the anti-inflammatory properties of natural products.

Now, a new phase of research can explore the development of drugs that will stem the development of dementias such as Alzheimer’s, which affects some 800,000 people in the UK, with 163,000 new cases a year being diagnosed. Globally, there are at least 44.4 million dementia sufferers, with the numbers expected to soar.

The key breakthrough by Dr Olajide and his co-researchers is to demonstrate that punicalagin, which is a polyphenol – a form of chemical compound – found in pomegranate fruit, can inhibit inflammation in specialised brain cells known as microglia. This inflammation leads to the destruction of more and more brain cells, making the condition of Alzheimer’s sufferers progressively worse.

There is still no cure for the disease, but the punicalagin in pomegranate could prevent it or slow down its development.

Dr Olajide worked with co-researchers – including four PhD students – in the University of Huddersfield’s Department of Pharmacy and with scientists at the University of Freiburg in Germany. The team used brain cells isolated from rats in order to test their findings. Now the research is published in the latest edition of the journal Molecular Nutrition & Food Research and Dr Olajide will start to disseminate his findings at academic conferences.

He is still working on the amounts of pomegranate that are required, in order to be effective.

"But we do know that regular intake and regular consumption of pomegranate has a lot of health benefits – including prevention of neuro-inflammation related to dementia," he says, recommending juice products that are 100 per cent pomegranate, meaning that approximately 3.4 per cent will be punicalagin, the compound that slows down the progression of dementia.

Dr Olajide states that most of the anti-oxidant compounds are found in the outer skin of the pomegranate, not in the soft part of the fruit. And he adds that although this has yet to be scientifically evaluated, pomegranate will be useful in any condition for which inflammation – not just neuro-inflammation – is a factor, such as rheumatoid arthritis, Parkinson’s and cancer.

The research continues and now Dr Olajide is collaborating with his University of Huddersfield colleague, the organic chemist Dr Karl Hemming. They will attempt to produce compound derivatives of punicalagin that could the basis of new, orally administered drugs that would treat neuro-inflammation.

Dr Olajide has been a Senior Lecturer at the University of Huddersfield for four years. His academic career includes a post as a Humboldt Postdoctoral Research Fellow at the Centre for Drug Research at the University of Munich. His PhD was awarded from the University of Ibadan in his native Nigeria, after an investigation of the anti-inflammatory properties of natural products.

He attributes this area of research to his upbringing. “African mothers normally treat sick children with natural substances such as herbs. My mum certainly used a lot of those substances. And then I went on to study pharmacology!”

Mind and body: Scientists identify immune system link to mental illness

Children with high everyday levels of a protein released into the blood in response to infection are at greater risk of developing depression and psychosis in adulthood, according to new research which suggests a role for the immune system in mental illness.

The study, published today in JAMA Psychiatry, indicates that mental illness and chronic physical illness such as coronary heart disease and type 2 diabetes may share common biological mechanisms.

When we are exposed to an infection, for example influenza or a stomach bug, our immune system fights back to control and remove the infection. During this process, immune cells flood the blood stream with proteins such as interleukin-6 (IL-6), a tell-tale marker of infection. However, even when we are healthy, our bodies carry trace levels of these proteins – known as ‘inflammatory markers’ – which rise exponentially in response to infection.

Now, researchers have carried out the first ever longitudinal study – a study that follows the same cohort of people over a long period of time – to examine the link between these markers in childhood and subsequent mental illness.

A team of scientists led by the University of Cambridge studied a sample of 4,500 individuals from the Avon Longitudinal Study of Parents and Children – also known as Children of the 90s – taking blood samples at age 9 and following up at age 18 to see if they had experienced episodes of depression or psychosis. The team divided the individuals into three groups, depending on whether their everyday levels of IL-6 were low, medium or high. They found that those children in the ‘high’ group were nearly two times more likely to have experienced depression or psychosis than those in the ‘low’ group.

Dr Golam Khandaker from the Department of Psychiatry at the University of Cambridge, who led the study, says: “Our immune system acts like a thermostat, turned down low most of the time, but cranked up when we have an infection. In some people, the thermostat is always set slightly higher, behaving as if they have a persistent low level infection – these people appear to be at a higher risk of developing depression and psychosis. It’s too early to say whether this association is causal, and we are carrying out additional studies to examine this association further.”

The research indicates that chronic physical illness such as coronary heart disease and type 2 diabetes may share a common mechanism with mental illness. People with depression and schizophrenia are known to have a much higher risk of developing heart disease and diabetes, and elevated levels of IL-6 have previously been shown to increase the risk of heart disease and type 2 diabetes.

Professor Peter Jones, Head of the Department of Psychiatry and senior author of the study, says: “Inflammation may be a common mechanism that influences both our physical and mental health. It is possible that early life adversity and stress lead to persistent increase in levels of IL-6 and other inflammatory markers in our body, which, in turn, increase the risk of a number of chronic physical and mental illness.”

Indeed, low birth weight, a marker of impaired foetal development, is associated with increased everyday levels of inflammatory markers as well as greater risks of heart disease, diabetes, depression and schizophrenia in adults.

This potential common mechanism could help explain why physical exercise and diet, classic ways of reducing risk of heart disease, for example, are also thought to improve mood and help depression. The group is now planning additional studies to confirm whether inflammation is a common link between chronic physical and mental illness.

The research also hints at interesting ways of potentially treating illnesses such as depression: anti-inflammatory drugs. Treatment with anti-inflammatory agents leads to levels of inflammatory markers falling to normal. Previous research has suggested that anti-inflammatory drugs such as aspirin used in conjunction with antipsychotic treatments may be more effective than just the antipsychotics themselves. A multicentre trial is currently underway, into whether the antibiotic minocycline, used for the treatment of acne, can be used to treat lack of enjoyment, social withdrawal, apathy and other so called negative symptoms in schizophrenia. Minocycline is able to penetrate the ‘blood-brain barrier’, a highly selective permeability barrier which protects the central nervous system from potentially harmful substances circulating in our blood.

The ‘blood-brain barrier’ is also at the centre of a potential puzzle raised by research such as today’s research: how can the immune system have an effect in the brain when many inflammatory markers and antibodies cannot penetrate this barrier? Studies in mice suggest that the answer may lie in the vagus nerve, which connects the brain to the abdomen. When activated by inflammatory markers in the gut, it sends a signal to the brain, where immune cells produce proteins such as IL-6, leading to increased metabolism (and hence decreased levels) of the ‘happiness hormone’ serotonin in the brain. Similarly, the signals trigger an increase in toxic chemicals such as nitric oxide, quinolonic acid, and kynurenic acid, which are bad for the functioning of nerve cells.

Sublime Microglia: Expanding Roles for the Guardians of the CNS

Recent findings challenge the concept that microglia solely function in disease states in the central nervous system (CNS). Rather than simply reacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculpt the structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity. These physiological functions of microglia in the normal CNS begin during development and persist into maturity. Here, we develop a conceptual framework for functions of microglia beyond neuroinflammation and discuss the rich repertoire of signaling and communication motifs in microglia that are critical both in pathology and for the normal physiology of the CNS.

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