Posts tagged neurodegenerative disorders
Posts tagged neurodegenerative disorders
Researchers from Inserm and the Université Lille/Université Lille Nord de France have recently used a neurodegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. This research was conducted on mice and is published in the Diabetes review: it corroborates the theory that metabolic anomalies contribute massively to the development of dementia.
In France, more than 860,000 people suffer from Alzheimer’s disease and related disorders, making them the largest cause of age-related loss of intellectual function. Cognitive impairments observed in Alzheimer’s disease result from the accumulation of abnormal tau proteins in nerve cells undergoing degeneration (see the picture below). We know that obesity, a major risk factor in the development of insulin resistance and type 2 diabetes, increases the risk of dementia during the aging process. However, the effects of obesity on ‘Taupathies’ (i.e. tau protein-related disorders), including Alzheimer’s disease, were not clearly understood. In particular, researchers assumed that insulin resistance played a major role in terms of the effects of obesity.
The “Alzheimer & Tauopathies” team from mixed research unit 837 (Inserm/Université Lille 2/Université Lille Nord de France) directed by Dr. Luc Buée, in collaboration with mixed research unit 1011 “Nuclear receptors, cardiovascular diseases and diabetes”, have just demonstrated, in mice, that obese subjects develop aggravated disorders. To achieve this result, young transgenic mice, who develop tau-related neurodegeneration progressively with age, were put on a high-fat diet for five months, leading to progressive obesity.
“At the end of this diet, the obese mice had developed an aggravated disorder both from the point of view of memory and modifications to the Tau protein”, explains David Blum, in charge of research at Inserm.
This study uses a neurodenegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. Furthermore, it indicates that insulin resistance is not the aggravating factor, as was suggested in previous studies.
“Our research supports the theory that environmental factors contribute massively to the development of this neurodegenerative disorder” underlines the researcher. “Our work is now focussing on identifying the factors responsible for this aggravation” he adds.
Fifty years after scientists first posed a question about protein folding, the search for answers has led to the creation of a full-fledged field of research that led to major advances in supercomputers, new materials and drug discovery, and shaped our understanding of the basic processes of life, including so-called “protein-folding diseases” such as Alzheimer’s, Parkinson’s and type II diabetes.
In a review article published in the Nov. 23, 2012 issue of the journal Science, Stony Brook University researchers reviewed the progress on a 50-year-old puzzle called the Protein Folding Problem. Ken Dill and Justin MacCallum of Stony Brook’s Louis and Beatrice Laufer Center for Physical and Quantitative Biology show how a community of scientific researchers rose to tackle a grand-challenge problem of very basic science that had no obvious payoff at the time.
“Protein folding is a quintessential basic science. There has been no specific commercial target, yet the collateral payoffs have been broad and deep,” the researchers said in their paper, The Protein Folding Problem, 50 Years On.
“We have learned that proteins fold rapidly because random thermal motions cause conformational changes leading energetically downhill toward the native structure, a principle that is captured in funnel-shaped energy landscapes. And thanks in part to the large Protein Data Bank of known structures, predicting protein structures is now far more successful than was thought possible in the early days. What began as three questions of basic science one half-century ago has now grown into the full-fledged research field of protein physical science.”
For the first time, scientists at Fred Hutchinson Cancer Research Center have defined key events that take place early in the process of cellular aging.
Together the discoveries, made through a series of experiments in yeast, bring unprecedented clarity to the complex cascade of events that comprise the aging process and pave the way to understanding how genetics and environmental factors like diet interact to influence lifespan, aging and age-related diseases such as cancer and neurodegenerative disorders.
The findings, including unexpected results that link aspects of aging and lifespan to a mechanism cells use to store nutrients, are described in the Nov. 21 issue of Nature by co-authors Daniel Gottschling, Ph.D., a member of the Hutchinson Center’s Basic Sciences Division, and Adam Hughes, Ph.D., a postdoctoral fellow in the Gottschling Lab.
The work began with Hughes and Gottschling searching for the source of age-related damage in mitochondria.
“Normally, mitochondria are beautiful, long tubes, but as cells get older, the mitochondria become fragmented and chunky,” said Gottschling, also an affiliate professor in the Department of Genome Sciences at the University of Washington. “The changes in shape seen in aging yeast cells are also observed in certain human cells, such as neurons and pancreatic cells, and those changes have been associated with a number of age-related diseases in humans.”
What causes mitochondria to become distorted and dysfunctional as cells age had long been a mystery, but Gottschling and Hughes have discovered that specific changes in the vacuole lead directly to their malfunctioning.The researchers found the acidity of a structure in yeast cells known as the vacuole is critical to aging and the functioning of mitochondria – the power plants of the cell. They also describe a novel mechanism, which may have parallels in human cells, by which calorie restriction extends lifespan.
Research led by Chu Chen, PhD, Associate Professor of Neuroscience at LSU Health Sciences Center New Orleans, has identified an enzyme called Monoacylglycerol lipase (MAGL) as a new therapeutic target to treat or prevent Alzheimer’s disease. The study was published online November 1, 2012 in the Online Now section of the journal Cell Reports.
The research team found that inactivation of MAGL, best known for its role in degrading a cannabinoid produced in the brain, reduced the production and accumulation of beta amyloid plaques, a pathological hallmark of Alzheimer’s disease. Inhibition of this enzyme also decreased neuroinflammation and neurodegeneration, and improved plasticity of the brain, learning and memory.
“Our results suggest that MAGL contributes to the cause and development of Alzheimer’s disease and that blocking MAGL represents a promising therapeutic target,” notes Dr. Chu Chen, who is also a member of the Department of Otolaryngology at LSU Health Sciences Center New Orleans.
The researchers blocked MAGL with a highly selective and potent inhibitor in mice using different dosing regimens and found that inactivation of MAGL for eight weeks was sufficient to decrease production and deposition of beta amyloid plaques and the function of a gene involved in making beta amyloid toxic to brain cells. They also measured indicators of neuroinflammation and neurodegeneration and found them suppressed when MAGL was inhibited. The team discovered that not only did the integrity of the structure and function of synapses associated with cognition remain intact in treated mice, but MAGL inactivation appeared to promote spatial learning and memory, measured with behavioral testing.
Alzheimer’s disease is a neurodegenerative disorder characterized by accumulation and deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, synaptic dysfunction, progressive deterioration of cognitive function and loss of memory in association with widespread nerve cell death. The most common cause of dementia among older people, more than 5.4 million people in the United States and 36 million people worldwide suffer with Alzheimer’s disease in its various stages. Unfortunately, the few drugs that are currently approved by the Food and Drug Administration have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods, and none has shown a clear effect on disease progression or prevention.
“There is a great public health need to discover new therapies to prevent and treat this devastating disorder,” Dr. Chen concludes. The research was supported by grants from the National Institutes of Health. In addition to scientists from LSU Health Sciences Center New Orleans, the research team also included investigators from the Massachusetts Institute of Technology.
Berkeley Lab Scientists Help Develop Promising Therapy for Huntington’s Disease
There’s new hope in the fight against Huntington’s disease. A group of researchers that includes scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have designed a compound that suppresses symptoms of the devastating disease in mice.
The compound is a synthetic antioxidant that targets mitochondria, an organelle within cells that serves as a cell’s power plant. Oxidative damage to mitochondria is implicated in many neurodegenerative diseases including Alzheimer’s, Parkinson’s, and Huntington’s.
The scientists administered the synthetic antioxidant, called XJB-5-131, to mice that have a genetic mutation that triggers Huntington’s disease. The compound improved mitochondrial function and enhanced the survival of neurons. It also inhibited weight loss and stopped the decline of motor skills, among other benefits. In short, the Huntington’s mice looked and behaved like normal mice.
Based on their findings, the scientists believe that XJB-5-131 is a promising therapeutic compound that deserves further investigation as a way to fight neurodegenerative diseases.
They report their research in a paper that appears online Nov. 1 in the journal Cell Reports.
Caffeine’s effect on the brain’s adenosine receptors visualized for the first time
Scans allow researchers to study the link between caffeine and neurodegenerative disorders.
Molecular imaging with positron emission tomography (PET) has enabled scientists for the first time to visualize binding sites of caffeine in the living human brain to explore possible positive and negative effects of caffeine consumption. According to research published in the November issue of The Journal of Nuclear Medicine, PET imaging with F-18-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (F-18-CPFPX) shows that repeated intake of caffeinated beverages throughout a day results in up to 50 percent occupancy of the brain’s A1 adenosine receptors.
“The effects of caffeine to the human body are generally attributed to the cerebral adenosine receptors. In the human brain the A1 adenosine receptor is the most abundant,” said David Elmenhorst, MD, lead author of “Caffeine Occupancy of Human Cerebral A1 Adenosine Receptors: In Vivo Quantification with F-18-CPFPX and PET.” “In vitro studies have shown that commonly consumed quantities of caffeine have led to a high A1 adenosine occupancy. Our study aimed to measure the A1 adenosine receptor occupancy with in vivo imaging.”
Stay-at-home transcription factor saves axons
The old saw that local actions can have global consequences holds true for neurons, too. Selvaraj et al. show that a transcription factor remains in the axon to help prevent neurodegeneration.
In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), neurons usually die in stages, with axons deteriorating first and the cells themselves perishing later. Axon degeneration may represent a turning point for patients, after which so much neuronal damage has accumulated that treatments won’t work. Researchers have tested several proteins for their ability to save axons. One of these molecules, ciliary neurotrophic factor (CNTF), rescues axons in rodents and extends their lives. But it caused severe side effects in patients during clinical trials. “Acting on the same pathway but farther downstream could be an ideal way to improve the situation for motor neuron disease” and possibly for other neurodegenerative diseases, says senior author Michael Sendtner.
To discover how CNTF works, Selvaraj et al. studied pmn mutant mice that mimic ALS. The researchers found that CNTF not only prevented the shrinkage of the rodents’ motor neurons, it also reduced the number of swellings along the axon that are markers of degeneration. Another sign that CNTF was beneficial was the movement of mitochondria, which continually shuttle back and forth along the axons of healthy motor neurons. In axons from pmn mice, stalled mitochondria were prevalent, but treatment with CNTF accelerated the organelles to normal speeds.
Amyotrophic lateral sclerosis, also called Lou Gehrig’s disease, is a devastatingly cruel neurodegenerative disorder that robs sufferers of the ability to move, speak and, finally, breathe. Now researchers at the Stanford University School of Medicine and San Francisco’s Gladstone Institutes have used baker’s yeast — a tiny, one-celled organism — to identify a chink in the armor of the currently incurable disease that may eventually lead to new therapies for human patients.
“Even though yeast and humans are separated by a billion years of evolution, we were able to use the power of yeast genetics to identify an unexpected potential drug target for ALS,” said Aaron Gitler, PhD, an associate professor of genetics at Stanford. “Many neurodegenerative disorders such as ALS, Parkinson’s and Alzheimer’s exhibit protein clumping or misfolding within the neurons that is thought to either cause or contribute to the conditions. We are trying to figure out why these proteins aggregate in neurons in the brain and spinal cord, and what happens when they do.”
In 2008, Gitler received a New Innovator award from the National Institutes of Health to use yeast as a model for understanding human neurodegenerative diseases and as a way to identify new targets for drug development.
Changes in the ability to smell and taste can be caused by a simple cold or upper respiratory tract infection, but they may also be among the first signs of neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Now, new research from the Perelman School of Medicine at the University of Pennsylvania has revealed an association between an impaired sense of smell and myasthenia gravis (MG), a chronic autoimmune neuromuscular disease characterized by fluctuating fatigue and muscle weakness. The findings are published in the latest edition of PLOS ONE.
Most humans experience five types of tastes: sweet, salty, sour, bitter, and savory. The sense of taste is mediated by taste receptor cells which are bundled in our taste buds. “Sour” and “bitter” taste sensations alert the body to harmful foods that have spoiled or are toxic. But based on genetics, up to 25 percent of the population cannot detect certain bitter flavors (non-tasters), 25 percent can detect exceedingly small quantities (super-tasters), and the rest of us fall somewhere between these two extremes.
So what exactly does drinking a cup of bitter coffee have to do with chronic sinus infections, which account for approximately 18-22 million physician visits in the U.S. each year? Recent investigations have shown that these taste receptors (T2Rs) are also found in both upper and lower human respiratory tissue, likely signaling a connection between activation of bitter tastes and the need to launch an immune response in these areas when they are exposed to potentially harmful bacteria and viruses.
“With this information in mind, we wanted to better understand the exact role that bitter taste receptors play in the upper airway, especially between these super and non-tasters,” says Noam Cohen, MD, PhD, assistant professor of Otorhinolaryngology: Head and Neck Surgery, staff physician at the Philadelphia VAMC, and senior author of the new study.
An early diagnosis protocol for Alzheimer’s has been designed by researchers at the Ionian University in Greece, opening the way for the prevention and more effective treatment of the neurodegenerative disorder, which shows rapid deterioration and constitutes growing concern for modern societies.
The tool for the early diagnosis and prevention of Alzheimer’s disease dysfunctions is unique and has already attracted the strong interest of domestic and foreign pharmaceutical companies.
The research scientists have found the indices and their correlations that lead to an early diagnosis of the disease, through a hybrid diagnostic protocol based on the assessment of individual data.
A year ago the scientific research team discovered the “electric thrombosis” phenomenon, a mechanism that explains a series of dysfunctions, in the inner membrane of mitochondria affecting their number and operation, largely related with Alzheimer’s.
The team continued the research further by studying the mitochondrial membrane superconductor properties and other measurable biological factors before coming up with the early diagnosis tool for the disease.