Posts tagged alzheimer's disease
Articles and news from the latest research reports.
Right target, but missing the bulls-eye for Alzheimer’s
Alzheimer’s disease is the most common cause of late-life dementia. The disorder is thought to be caused by a protein known as amyloid-beta, or Abeta, which clumps together in the brain, forming plaques that are thought to destroy neurons. This destruction starts early, too, and can presage clinical signs of the disease by up to 20 years.
For decades now, researchers have been trying, with limited success, to develop drugs that prevent this clumping. Such drugs require a “target” — a structure they can bind to, thereby preventing the toxic actions of Abeta.
Now, a new study out of UCLA suggests that while researchers may have the right target in Abeta, they may be missing the bull’s-eye. Reporting in the Jan. 23 issue of the Journal of Molecular Biology, UCLA neurology professor David Teplow and colleagues focused on a particular segment of a toxic form of Abeta and discovered a unique hairpin-like structure that facilitates clumping.
"Every 68 seconds, someone in this country is diagnosed with Alzheimer’s," said Teplow, the study’s senior author and principal investigator of the NIH-sponsored Alzheimer’s Disease Research Center at UCLA. "Alzheimer’s disease is the only one of the top 10 causes of death in America that cannot be prevented, cured or even slowed down once it begins. Most of the drugs that have been developed have either failed or only provide modest improvement of the symptoms. So finding a better pathway for these potential therapeutics is critical."
The Abeta protein is composed of a sequence of amino acids, much like “a pearl necklace composed of 20 different combinations of different colors of pearl,” Teplow said. One form of Abeta, Abeta40, has 40 amino acids, while a second form, Abeta42, has two extra amino acids at one end.
Abeta42 has long been thought to be the toxic form of Abeta, but until now, no one has understood how the simple addition of two amino acids made it so much more toxic than Abeta40.
In his lab, Teplow and his colleagues used computer simulations in which they looked at the structure of the Abeta proteins in a virtual world. The researchers first created a virtual Abeta peptide that only contained the last 12 amino acids of the entire 42–amino-acid-long Abeta42 protein. Then, said Teplow, “we just let the molecule move around in a virtual world, letting the laws of physics determine how each atom of the peptide was attracted to or repulsed by other atoms.”
By taking thousands of snapshots of the various molecular structures the peptides created, the researchers determined which structures formed more frequently than others. From those, they then physically created mutant Abeta peptides using chemical synthesis.
"We studied these mutant peptides and found that the structure that made Abeta42 Abeta42 was a hairpin-like turn at the very end of the peptide of the whole Abeta protein," Teplow said.
The hairpin turn structure was not previously known in the detail revealed by the researchers, “so we feel our experiments were novel,” he said. “Our lab is the first to show that it is this specific turn that accounts for the special ability of Abeta42 to aggregate into clumps that we think kills neurons. Abeta40, the Abeta protein with two less amino acids at the end of the protein, did not do the same thing.”
Hopefully, the work of the Teplow laboratory presents what may the most relevant target yet for the development of drugs to fight Alzheimer’s disease, the researchers said.
(Source: uclahealth.org)
Less tau reduces seizures and sudden death in severe epilepsy
Deleting or reducing expression of a gene that carries the code for tau, a protein associated with Alzheimer’s disease, can prevent seizures in a severe type of epilepsy linked to sudden death, said researchers at Baylor College of Medicine and the Mayo Clinic in Jacksonville, Fla., in a report in the current issue of the Journal of Neuroscience.
A growing understanding of the link between epilepsy and some forms of inherited Alzheimer’s disease led to the finding that could point the way toward new drugs for seizure disorders said Dr. Jeffrey Noebels, professor of neurology at BCM, and director of the Blue Bird Circle Developmental Neurogenetics Laboratory.
In her research, Jerrah Holth, a graduate student in molecular and human genetics at BCM who was working with mice with the severe form of epilepsy in Noebel’s laboratory, deleted the gene for tau. She found that reducing or eliminating tau also prevented the seizures in a severe form of epilepsy that has been associated with sudden death and reduced deaths in the animals.
In an earlier experiment, Noebels, in collaboration with Dr. Lennart Mucke at the Gladstone Research Laboratory at the University of California San Francisco, found that mice who carried a human gene that leads to accumulation of the beta amyloid protein and the amyloid plaques that accumulate in the brains of people with Alzheimer’s disease, also had epileptic seizures arising in the hippocampus, the region of the brain associated with memory storage and retrieval.
"This led to the paradigm-shifting hypothesis that excessive neuronal network activity, rather than too little, may contribute to lower cognitive performance and dementia in some forms of Alzheimer’s disease. When this happens, the progression of memory loss may accelerate," said Noebels.
The finding also demonstrated the two disorders may share defects in signaling within brain memory circuits.
The two labs went on to show that deleting the second gene for tau ameliorated both cognitive losses and seizures in the mice whose inherited disorder mimicked Alzheimer’s disease found in humans.
Holth’s finding demonstrates that tau is involved in a far broader range of epilepsy than previously suspected, said Noebels. The type of epilepsy she studied resulted from an inherited potassium ion channel defect that affects the flow of the potassium in and out of nerve cells. She found that removing the gene encoding Tau not only dramatically reduced seizures, but prevented the mice from dying early, which typically happens in these animals.
"Even a partial reduction of the amount of tau protein by 50 percent was highly effective," said Holth. Her finding suggests developing new drugs that lower the normal interactions of the tau protein may reduce seizures and sudden unexpected death for persons with intractable epilepsies, a problem in nearly one-third of the 5 million Americans with this disorder.
Currently, Noebels and his colleagues in the Blue Bird Laboratory are studying whether the loss of tau can correct a seizure disorder once it is already established. If these studies prove fruitful, “the pharmacological discovery programs under development for treatment of Alzheimer’s disease may one day find their way to the epilepsy clinic,” said Noebels.
(Image: ALAMY)
Alzheimer’s researchers trying brain zaps
It has the makings of a science fiction movie: zap someone’s brain with mild jolts of electricity to try to stave off the creeping memory loss of Alzheimer’s disease.
And it’s not easy. Holes are drilled into the patient’s skull so tiny wires can be implanted into just the right spot.
A dramatic shift is beginning in the frustrating struggle to find something to slow the damage of this epidemic: The first U.S. experiments with “brain pacemakers” for Alzheimer’s are getting under way. Scientists are looking beyond drugs to implants in the hunt for much-needed new treatments.
The research is in its infancy. Only a few dozen people with early-stage Alzheimer’s will be implanted in a handful of hospitals. No one knows if it might work, and if it does, how long the effects might last.
Kathy Sanford was among the first to sign up. The Ohio woman’s early-stage Alzheimer’s was gradually getting worse. She still lived independently, posting reminders to herself, but no longer could work. Medications weren’t helping.
Major step toward an Alzheimer’s vaccine
A team of researchers from Université Laval, CHU de Québec, and pharmaceutical firm GlaxoSmithKline (GSK) has discovered a way to stimulate the brain’s natural defense mechanisms in people with Alzheimer’s disease. This major breakthrough, details of which are presented today in an early online edition of the Proceedings of the National Academy of Sciences (PNAS), opens the door to the development of a treatment for Alzheimer’s disease and a vaccine to prevent the illness.
One of the main characteristics of Alzheimer’s disease is the production in the brain of a toxic molecule known as amyloid beta. Microglial cells, the nervous system’s defenders, are unable to eliminate this substance, which forms deposits called senile plaques.
The team led by Dr. Serge Rivest, professor at Université Laval’s Faculty of Medicine and researcher at the CHU de Québec research center, identified a molecule that stimulates the activity of the brain’s immune cells. The molecule, known as MPL (monophosphoryl lipid A), has been used extensively as a vaccine adjuvant by GSK for many years, and its safety is well established.
In mice with Alzheimer’s symptoms, weekly injections of MPL over a twelve-week period eliminated up to 80% of senile plaques. In addition, tests measuring the mice’s ability to learn new tasks showed significant improvement in cognitive function over the same period.
The researchers see two potential uses for MPL. It could be administered by intramuscular injection to people with Alzheimer’s disease to slow the progression of the illness. It could also be incorporated into a vaccine designed to stimulate the production of antibodies against amyloid beta. “The vaccine could be given to people who already have the disease to stimulate their natural immunity,” said Serge Rivest. “It could also be administered as a preventive measure to people with risk factors for Alzheimer’s disease.”
"When our team started working on Alzheimer’s disease a decade ago, our goal was to develop better treatment for Alzheimer’s patients," explained Professor Rivest. "With the discovery announced today, I think we’re close to our objective."
(Photo: ALAMY)
First Alzheimer’s case has full diagnosis 106 years later
More than a hundred years after Alois Alzheimer identified Alzheimer’s disease in a patient an analysis of that original patient’s brain has revealed the genetic origin of their condition.
The brain specimen tested was discovered in a university basement late last century after a search by rival teams of academics.
"It is extremely satisfying to place this last piece in the medical puzzle that Auguste Deter, the first ever Alzheimer patient, presented us with,” said Professor Manuel Graeber, from the University of Sydney.
"It is not only of historical interest, however, as it ends any speculation about whether the disease is correctly named after Alois Alzheimer. Alzheimer’s ability to recognise this dementia more than a century ago provides compelling support for specialisation in medicine. Alzheimer was a founding father of neuropathology, an important medical specialty that is still underrepresented."
Professor Graeber, from the University’s Brain and Mind Research Institute, Sydney Medical School and the Faculty of Health Sciences, collaborated with Professor Ulrich Müller’s team from the Institute of Human Genetics of the University of Giessen in Germany to produce the molecular diagnosis recently published in Lancet Neurology.
For years scientists have been wondering whether the first case of Alzheimer’s disease had a genetic cause. In 1901 Auguste Deter, a middle-aged female patient at the Frankfurt Asylum with unusual symptoms, including short-term memory loss, came to the attention of Dr Alzheimer. When she died, Dr Alzheimer examined her brain and described the distinctive damage indicating a form of presenile dementia.
For decades the more than 200 slides that Alzheimer prepared from Deter’s brain were lost. Then in 1992, after Professor Graeber uncovered new information pointing to their location, two teams of medical researchers began a dramatic race to find them.
One team searched in Frankfurt but it was a team headed by Professor Graeber, then working at the Max Planck Institute for Neurobiology that finally located the material at the University of Munich in 1997.
The slides were examined and confirmed beyond doubt that Deter was suffering from Alzheimer’s disease, with large numbers of amyloid plaques and neurofribrillary tangles in the brain that are hallmarks of the disease. Until now a more sophisticated DNA analysis of the small amount of fragile material in single slides has not been possible.
Since their rediscovery, a significant number of brain slides have been under the official custodianship of Professor Graeber who has been at the University of Sydney since 2010. He is preparing a book on the material.
"We found a mutation whose ultimate effect is the formation of amyloid plaques. These plaques, which form between nerve cells and seem to suffocate them are the key diagnostic landmark of the disease."
Alzheimer’s disease represents one of the greatest health problems in industrialised societies today. An estimated 100 million dementia sufferers are predicted worldwide by 2050, the vast majority of whom will have Alzheimer’s disease.
95 percent of Alzheimer’s patients suffer late onset of the illness after they turn 65. Five percent fall ill before that age (early onset) and Auguste Deter belongs to this group.
"We have revealed that Auguste Deter is one of those in which early onset of the disease is caused by mutation in a single gene," said Professor Graeber.
Detrimental effect of obesity on lesions associated with Alzheimer’s disease
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.
Can Blood Pressure Drugs Reduce the Risk of Dementia?
People taking the blood pressure drugs called beta blockers may be less likely to have changes in the brain that can be signs of Alzheimer’s disease and other types of dementia, according to a study released today that will be presented at the American Academy of Neurology’s 65th Annual Meeting in San Diego, March 16 to 23, 2013. The study involved 774 elderly Japanese-American men who took part in the Honolulu-Asia Aging Study. Autopsies were performed on the men after their death. Of the 774 men, 610 had high blood pressure or were being treated with medication for high blood pressure. Among those who had been treated (about 350), 15 percent received only a beta blocker medication, 18 percent received a beta blocker plus one or more other medications, and the rest of the participants received other blood pressure drugs.
The study found that all types of blood pressure treatments were clearly better than no treatment. However, men who had received beta blockers as their only blood pressure medication had fewer abnormalities in their brains compared to those who had not been treated for their hypertension, or who had received other blood pressure medications. The brains of participants who had received beta blockers plus other medications showed an intermediate reduction in numbers of brain abnormalities.
These included two distinct types of brain lesion: those indicating Alzheimer’s disease, and lesions called microinfarcts, usually attributed to tiny, multiple, unrecognized strokes. Study participants who had taken beta blockers alone or in combination with another blood pressure medication had significantly less shrinkage in their brains.
“With the number of people with Alzheimer’s disease expected to grow significantly as our population ages, it is increasingly important to identify factors that could delay or prevent the disease,” said study author Lon White, MD, of the Pacific Health Research and Education Institute in Honolulu. “These results are exciting, especially since beta blockers are a common treatment for high blood pressure.”
Earlier research has shown that high blood pressure in midlife is a strong risk factor for dementia.
Promising compound restores memory loss and reverses symptoms of Alzheimer’s
A new ray of hope has broken through the clouded outcomes associated with Alzheimer’s disease. A new research report published in January 2013 print issue of The FASEB Journal by scientists from the National Institutes of Health shows that when a molecule called TFP5 is injected into mice with disease that is the equivalent of human Alzheimer’s, symptoms are reversed and memory is restored—without obvious toxic side effects.
"We hope that clinical trial studies in AD patients should yield an extended and a better quality of life as observed in mice upon TFP5 treatment," said Harish C. Pant, Ph.D., a senior researcher involved in the work from the Laboratory of Neurochemistry at the National Institute of Neurological Disorders at Stroke at the National Institutes of Health in Bethesda, MD. "Therefore, we suggest that TFP5 should be an effective therapeutic compound."
To make this discovery, Pant and colleagues used mice with a disease considered the equivalent of Alzheimer’s. One set of these mice were injected with the small molecule TFP5, while the other was injected with saline as placebo. The mice, after a series of intraperitoneal injections of TFP5, displayed a substantial reduction in the various disease symptoms along with restoration of memory loss. In addition, the mice receiving TFP5 injections experienced no weight loss, neurological stress (anxiety) or signs of toxicity. The disease in the placebo mice, however, progressed normally as expected. TFP5 was derived from the regulator of a key brain enzyme, called Cdk5. The over activation of Cdk5 is implicated in the formation of plaques and tangles, the major hallmark of Alzheimer’s disease.
"The next step is to find out if this molecule can have the same effects in people, and if not, to find out which molecule will," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. “Now that we know that we can target the basic molecular defects in Alzheimer’s disease, we can hope for treatments far better – and more specific – than anything we have today.”
(Source: eurekalert.org)
Houston, We Have Another Problem: Study Shows that Space Travel is Harmful to the Brain
As if space travel was not already filled with enough dangers, a new study out today in the journal PLOS ONE shows that cosmic radiation – which would bombard astronauts on deep space missions to places like Mars – could accelerate the onset of Alzheimer’s disease.
“Galactic cosmic radiation poses a significant threat to future astronauts,” said M. Kerry O’Banion, M.D., Ph.D., a professor in the University of Rochester Medical Center (URMC) Department of Neurobiology and Anatomy and the senior author of the study. “The possibility that radiation exposure in space may give rise to health problems such as cancer has long been recognized. However, this study shows for the first time that exposure to radiation levels equivalent to a mission to Mars could produce cognitive problems and speed up changes in the brain that are associated with Alzheimer’s disease.”
While space is full of radiation, the earth’s magnetic field generally protects the planet and people in low earth orbit from these particles. However, once astronauts leave orbit, they are exposed to constant shower of various radioactive particles. With appropriate warning, astronauts can be shielded from dangerous radiation associated with solar flares. But there are also other forms of cosmic radiation that, for all intents and purposes, cannot be effectively blocked.
Because this radiation exists in low levels, the longer an astronaut is in deep space, the greater the exposure. This is a concern for NASA as the agency is planning manned missions to a distant asteroid in 2021 and to Mars in 2035. The round trip to the red planet, in particular, could take as long as three years.
For over 25 years, NASA has been funding research to determine the potential health risks of space travel in an effort to both develop countermeasures and determine whether or not the risks warranted sending men and women on extended missions in deep space.
Since that time, several studies have demonstrated the potential cancer, cardiovascular, and musculoskeletal impact of galactic cosmic radiation. The study out today for the first time examines the potential impact of space radiation on neurodegeneration, in particular, the biological processes in the brain that contribute to the development of Alzheimer’s disease. O’Banion – whose research focuses on how radiation affects the central nervous system – and his team have been working with NASA for over eight years.
The researchers studied the impact of a particular form of radiation called high-mass, high-charged (HZE) particles. These particles – which are propelled through space at very high speeds by the force of exploding stars – come in many different forms. For this study the researcher chose iron particles. Unlikely hydrogen protons, which are produced by solar flares, the mass of HZE particles like iron, combined with their speed, enable them to penetrate solid objects such as the wall and protective shielding of a spacecraft.
“Because iron particles pack a bigger wallop it is extremely difficult from an engineering perspective to effectively shield against them,” said O’Banion. “One would have to essentially wrap a spacecraft in a six-foot block of lead or concrete.”
Alzheimer’s Muddles Memory of How Things Work
Which is bigger, a key or an ant? That question might be easy for you to answer quickly, but it could be a little more confusing for a person with Alzheimer’s.
The most obvious trait of the mind-ruining disease is memory loss, with patients forgetting once-familiar people, places and experiences. New research shows how this mental deterioration extends to semantic memory, which has more to do with remembering facts and concepts and underlies a basic understanding of how things works.
For their study, researchers recruited 70 cognitively healthy people, 27 patients with Alzheimer’s 25 patients with mild cognitive impairment (MCI), often considered a precursor to dementia. All were tested on their ability to make size judgments about two pictures shown to them — the premise being that the bigger the difference in size between two objects, the faster a person would be able to answer the question.
"If you ask someone what is bigger, a key or an ant, they would be slower in their response than if you asked them what is bigger, a key or a house," researcher Terry Goldberg, of the Hofstra North Shore-LIJ School of Medicine, said in a statement.
This held true in the experiments, but the MCI and Alzheimer’s patients had much more trouble when asked to respond to a task with small size differences.
The experiment was then tweaked so that the participants were shown pictures of a small ant and a big house or a big ant and a small house. The MCI and Alzheimer’s patients did not have a problem making judgments about the small ant and big house, but had trouble with the more incongruent set. They were confused about which object was actually larger when shown a big ant and a small house, and were more likely to answer incorrectly or take longer to arrive at a response, the researchers said.
Goldberg said the findings indicate “that something is slowing down the patient and it is not episodic memory but semantic memory.”
The team will continue to study these patients over time to see if these semantic problems get worse as the disease advances.