Abstract
UC Davis researchers create molecule that blocks pathway leading to Alzheimer's disease
UC Davis researchers have found novel compounds that disrupt the formation of amyloid, the clumps of protein in the brains of people with Alzheimer's disease believed to be important in causing the disease's characteristic mental decline. The so-called “spin-labeled fluorene compounds” are an important new target for researchers and physicians focused on diagnosing, treating and studying the disease.
The study, published today in the online journal PLoS ONE, is entitled “The influence of spin-labeled fluorene compounds on the assembly and toxicity of the Aβ peptide.”
“We have found these small molecules to have significant beneficial effects on cultured neurons, from protecting against toxic compounds that form in neurons to reducing inflammatory factors,” said John C. Voss, professor of biochemistry and molecular medicine at the UC Davis School of Medicine and the principal investigator of the study. “As a result, they have great potential as a therapeutic agent to prevent or delay injury in individuals in the earliest stages of Alzheimer's disease, before significant damage to the brain occurs.”
Amyloid is an accumulation of proteins and peptides that are otherwise found naturally in the body. One component of amyloid − the amyloid beta (Aβ) peptide − is believed to be primarily responsible for destroying neurons in the brain. Fluorene compounds, which are small three-ringed molecules, originally were developed as imaging agents to detect amyloid with PET imaging. In addition to being excellent for detecting amyloid, fluorenes bind and destabilize Aβ peptide and thereby reduce amyloid formation, according to previous findings in mice by Lee-Way Jin, another study author and associate professor in the UC Davis MIND Institute and Department of Medical Pathology and Laboratory Medicine.
The current research studied the effects of fluorene compounds by attaching a special molecule to make their activity evident using electron paramagnetic resonance (EPR) spectroscopy. This technology allows researchers to observe very specific activities of molecules of interest because biological tissues do not emit signals detectable by EPR. Since Voss was interested in the activity of fluorenes, he added a nitroxide “spin label,” a chemical species with a unique signal that can be measured by EPR.
The group found that spin-labeled compounds disrupted Aβ peptide formation even more effectively than did non-labeled fluorenes. In addition, the antioxidant properties of the nitroxide, which scavenge reactive oxygen species known to damage neurons and increase inflammation, significantly contributed to the protective effects on neurons.
“The spin-labeled fluorenes demonstrated a number of extremely important qualities: They are excellent for detecting amyloid in imaging studies, they disrupt Aβ formation, and they reduce inflammation,” said Voss. “This makes them potentially useful in the areas of research, diagnostics and treatment of Alzheimer's disease.”
Alzheimer's disease is the most common form of dementia and affects some 5 million Americans. Current medications used to fight the disease usually have only small and temporary benefits, and commonly have many side effects.
A major obstacle in developing Alzheimer's disease therapy is that most molecules will not cross the blood-brain barrier, so that potential treatments given orally or injected into the bloodstream cannot enter the brain where they are needed. Fluorene compounds are small molecules that have been shown to penetrate the brain well.
“We have brought together expertise from diverse fields to get to this point, and what was once a side interest has become a major focus,” said Voss. “We are very excited and hopeful that these unique compounds can become extremely important.“
Voss' group next plans to study the safety of spin-labeled fluorene compounds as well as their efficacy for treating models of Alzheimer's disease in small animals. (Source: EurekAlert! A service of AAAS and University of California - Davis Health System).
New MRI technique may predict progress of dementias
Computer modeling supports theory that many dementias spread like prion diseases
A new technique for analyzing brain images offers the possibility of using magnetic resonance imaging (MRI) to predict the rate of progression and physical path of many degenerative brain diseases, report scientists at the San Francisco VA Medical Center and the University of California, San Francisco.
The technique, developed by SFVAMC scientists in collaboration with a team led by Bruce Miller, MD, clinical director of the UCSF Memory and Aging Center, also supports mounting evidence that dementias spread through the brain along specific neuronal pathways in the same manner as prion diseases (see related UCSF story).
The scientists employed new computer modeling techniques to realistically predict the physical progression of Alzheimer's disease and frontotemporal dementia (FTD) using images of 14 healthy brains. The models were based on whole-brain tractography, an MRI technique that maps the neural pathways, or “communication wires,” that connect different areas of the brain. The spread of disease along those pathways, as predicted by the models, closely matched actual MRI images of brain degeneration in 18 Alzheimer's patients and 18 FTD patients. Their study was published in the March 22 edition of Neuron.
“The results need to be replicated, but they suggest that, by using this approach, we can predict the location and course of future brain atrophy in Alzheimer's, FTD and other degenerative brain diseases, based on just one MRI taken at the outset of the disease,” said senior author Michael Weiner, MD, director of the SFVAMC Center for Imaging of Neurodegenerative Diseases. “This would be extremely useful in planning treatment, and in helping patients and families know what to expect as dementia progresses.”
Weiner, who is also a UCSF professor of radiology, medicine, psychiatry and neurology, said that the results were “consistent with an emerging concept that brain damage occurs in these neurodegenerative diseases in a diffusive, prion-like propagation.”
A prion is an infectious, misfolded form of a normal protein. These proteins leave destructive amyloid deposits in the brains in which they develop, causing degeneration and eventual death. They are responsible for Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy, or “mad cow” disease, in cattle. In 1997, neurologist Stanley B. Prusiner of UCSF was awarded the Nobel Prize in Medicine for discovering and characterizing the prion. His finding overturned a tenet of modern biology, showing that a protein, rather than just the molecules DNA and RNA, could cause infection.
“The idea of a prion-like mode of progression in dementias, which many scientists are beginning to support, is that the misfolded protein in one neuron will infect a neighboring brain cell, causing proteins in that cell to misfold in turn, and that the spread of these misfolded proteins flows along certain networks in the brain,” explained Weiner. “For instance, in Alzheimer's, there is a spread of amyloid protein along the memory network. This paper reinforces the idea that the damage occurs progressively along that network and others.”
Weiner emphasized that Alzheimer's and frontotemporal dementia “are not infectious diseases” like Creutzfeldt-Jakob. But he said “it may be that a little seed of the disease begins in one neuron in the brain and spreads in a similar way – so it's infectious within the brain, from one neuron to the next.” (Source: EurekAlert! A service of AAAS and University of California – San Francisco).
People with dementia have more preventable hospitalizations
Group Health-University of Washington research in JAMA
SEATTLE–Compared to individuals without dementia, people who subsequently developed dementia had a significantly higher rate of hospital admissions for all causes. They also had more admissions for “ambulatory care-sensitive” conditions, for which proactive care may have prevented hospitalizations. This suggests opportunities for improving outpatient care of seniors with dementia, according to research in the January 11 Journal of the American Medical Association.
“Nonelective hospitalization of older people, particularly those with dementia, is not a trivial event,“ wrote first author Elizabeth A. Phelan, MD, MS, an associate professor in gerontology and geriatric medicine at the University of Washington (UW) School of Medicine, associate director of the UW Health Promotion Research Center at the UW School of Public Health, and an affiliate investigator at Group Health Research Institute.
“Among older persons without dementia, hospitalization for serious illness is associated with subsequent cognitive decline,” Dr. Phelan wrote. During an inpatient stay, frail elders, including those with dementia, are at increased risk of delirium, functional decline, and (iatrogenic) complications induced by a physician's activity, manner, or therapy. “Identifying conditions that precipitate hospitalization of elderly individuals with dementia could focus clinical priorities on secondary and tertiary prevention in the outpatient setting and improve health care for this vulnerable and increasing population.”
Dr. Phelan and colleagues at the UW and Group Health conducted research to determine whether dementia onset is associated more hospitalization—or with different reasons for it, particularly ambulatory care-sensitive conditions, for which proactive outpatient care might have prevented the need for a hospital stay. This research is based on the joint Group Health-UW Adult Changes in Thought (ACT) study, led by Dr. Phelan's coauthor Eric B. Larson, MD, MPH, Group Health's vice president for research and the executive director of Group Health Research Institute.
The research analyzed hospitalizations among 3,019 participants in the ACT study. ACT studies adults aged 65 years or older enrolled in Group Health, an integrated health care system. All participants had no dementia at the beginning of the study, and those who eventually had a dementia diagnosis as part of dementia screening contributed non-dementia hospitalizations until their diagnosis. Automated data were used to identify all hospitalizations of all participants from time of enrollment in ACT until death, disenrollment from Group Health, or end of follow-up, whichever came first.
During the study period, from February 1994 to December 2007, admissions totaled 5,328. Of the participants, 494 individuals eventually developed dementia, and 427 (86 percent) of those were admitted to a hospital at least once. Of the 2,525 people who remained free of dementia, 1,478 (59 percent) were admitted at least once. Those who developed dementia had 689 admissions before and 714 after dementia diagnosis. The average annual admission rate among participants with dementia was more than twice that of those without dementia. In the fully adjusted model, admission rates were significantly higher among participants with dementia compared with those without dementia for five types of disorders: circulatory, genitourinary, infectious, neurological, and respiratory.
The crude admission rate for ambulatory care-sensitive conditions was higher among those with dementia. Admissions for these conditions accounted for 28 percent of all hospitalizations among those with dementia vs. only 19 percent of all admissions among those who remained dementia free. People who developed dementia had 121 admissions for ambulatory care-sensitive conditions before and 198 after dementia diagnosis. Forty percent (196) of the dementia group had at least one admission for an ambulatory care-sensitive condition, compared with 17 percent (424) of the dementia-free group.
Three ambulatory care-sensitive conditions—bacterial pneumonia, congestive heart failure, and urinary tract infection—accounted for two-thirds of all potentially preventable admissions, and admission rates among those with dementia were significantly higher for all three conditions. “Admission rates for dehydration and duodenal ulcer, though low overall, were also significantly higher among those with dementia,” the authors wrote.
Knowing which ambulatory care-sensitive conditions are most likely to lead to hospitalization may help clinicians focus their differential diagnosis and permit proactive, early management for these conditions among patients with dementia, according to the authors. “Early detection and outpatient management of acute illness when it is still in its early phases,” they wrote, “might minimize the need for hospitalization for these conditions and help health care organizations reduce” their rates of admissions for ambulatory care-sensitive conditions—and associated costs.
The researchers concluded that their findings suggest “important opportunities for improving care of demented older persons, including developing better strategies for delivering anticipatory, proactive primary care to this population. The characteristic feature of late-life dementia—cognitive impairment in the face of multiple other comorbidities—presents a special challenge not currently addressed in models of chronic disease care.” (Source: EurekAlert! A service of AAAS and Group Health Research Institute).
Eating fish, chicken, nuts may lower risk of Alzheimer's disease
MINNEAPOLIS – A new study suggests that eating foods that contain omega-3 fatty acids, such as fish, chicken, salad dressing and nuts, may be associated with lower blood levels of a protein related to Alzheimer's disease and memory problems. The research is published in the May 2, 2012, online issue of Neurology ®, the medical journal of the American Academy of Neurology.
“While it's not easy to measure the level of beta-amyloid deposits in the brain in this type of study, it is relatively easy to measure the levels of beta-amyloid in the blood, which, to a certain degree, relates to the level in the brain,” said study author Nikolaos Scarmeas, MD, MS, with Columbia University Medical Center in New York and a member of the American Academy of Neurology.
For the study, 1,219 people older than age 65, free of dementia, provided information about their diet for an average of 1.2 years before their blood was tested for the beta-amyloid. Researchers looked specifically at 10 nutrients, including saturated fatty acids, omega-3 and omega-6 polyunsaturated fatty acids, mono-unsaturated fatty acid, vitamin E, vitamin C, beta-carotene, vitamin B12, folate and vitamin D.
The study found that the more omega-3 fatty acids a person took in, the lower their blood beta-amyloid levels. Consuming one gram of omega-3 per day (equal to approximately half a fillet of salmon per week) more than the average omega-3 consumed by people in the study is associated with 20 to 30 percent lower blood beta-amyloid levels.
Other nutrients were not associated with plasma beta-amyloid levels. The results stayed the same after adjusting for age, education, gender, ethnicity, amount of calories consumed and whether a participant had the APOE gene, a risk factor for Alzheimer's disease.
“Determining through further research whether omega-3 fatty acids or other nutrients relate to spinal fluid or brain beta-amyloid levels or levels of other Alzheimer's disease related proteins can strengthen our confidence on beneficial effects of parts of our diet in preventing dementia,“ said Scarmeas. (Source: EurekAlert! A service of AAAS and American Academy of Neurology).
Scientists reveal early diagnostic clues for AD using advanced brain imaging technology
Amsterdam, NL, May 2, 2012 – Alzheimer's disease (AD) is a major neurodegenerative disorder that affects millions of people worldwide. New and accurate techniques for early diagnosis are critical. Pravat K. Mandal, PhD, and his colleagues have developed a completely non-invasive brain imaging technique to measure specific brain chemical changes. This provides a signature of the early stages of AD from the hippocampal region of the brain. Their work is reported in the Journal of Alzheimer's Disease.
“Alzheimer's disease has become a silent tsunami in the aging population,” says Dr. Mandal, who is associated with the National Brain Research Center, Gurgaon, India, and Johns Hopkins University School of Medicine. “This discovery of a diagnostic technique that requires no blood work or radiation, and that can be conducted in less than fifteen minutes, may offer hope to Alzheimer's disease patients and their families.”
Dr. Mandal and his co-investigators studied the brains of normal controls, AD patients, and patients with mild cognitive impairment (MCI) using multi-voxel 31P magnetic resonance spectroscopy (MRS) imaging, along with an advanced analytical tool, to assess brain chemistry in the hippocampal regions. They observed during the course of their study that the left hippocampus becomes alkaline in AD patients, which is in contrast to the normal aging process in which the brain tends to be more acidic.
Dr. Mandal and his colleagues also identified four brain chemicals that change significantly in pre-Alzheimer and Alzheimer disease patients compared to normal subjects. They are phosphomonoester (PME), the building block of neuronal membrane; phosphodiester (PDE), the membrane degradation product; phosphocreatine (PCr), stored energy for brain functioning; and adenosine triphosphate (γ-ATP), the source of brain energy. The level of PME is significantly decreased in the left hippocampal areas of these patients, and the levels of PDE, PCr, and γ-ATP are increased.
“In the left hippocampus the increase in pH to the alkaline range, along with statistically significant increases in PDE, PCr, and γ-ATP and decreases in PDE, serve as a promising new biomarker for AD,” notes Dr. Mandal. He and his colleagues plan to conduct longitudinal studies with Alzheimer and Parkinson patients with larger sample sizes to investigate specificity of their test. “It is our hope that such clinical research, using state-of-the-art technology, may give new hope to cognitively impaired patients for an earlier and more predictable AD diagnosis.”(Source: EurekAlert! A service of AAAS and IOS Press).
Scientists gain new understanding of Alzheimer's trigger
May 2, 2012 — A highly toxic beta-amyloid – a protein that exists in the brains of Alzheimer's disease victims – has been found to greatly increase the toxicity of other more common and less toxic beta-amyloids, serving as a possible “trigger” for the advent and development of Alzheimer's, researchers at the University of Virginia and German biotech company Probiodrug have discovered.
The finding, reported in the May 2 online edition of the journal Nature, could lead to more effective treatments for Alzheimer's. Already, Probiodrug AG, based in Halle, Germany has completed phase 1 clinical trials in Europe with a small molecule that inhibits an enzyme, glutaminyl cyclase, that catalyzes the formation of this hypertoxic version of beta-amyloid.
“This form of beta-amyloid, called pyroglutamylated (or pyroglu) beta-amyloid, is a real bad guy in Alzheimer's disease,” said principal investigator George Bloom, a U.Va. professor of biology and cell biology in the College of Arts & Sciences and School of Medicine, who is collaborating on the study with scientists at Probiodrug. “We've confirmed that it converts more abundant beta-amyloids into a form that is up to 100 times more toxic, making this a very dangerous killer of brain cells and an attractive target for drug therapy.”
Bloom said the process is similar to various prion diseases, such as mad cow disease or chronic wasting disease, where a toxic protein can “infect“ normal proteins that spread through the brain and ultimately destroy it.
In the case of Alzheimer's, severe dementia occurs over the course of years prior to death.
“You might think of this pyroglu beta-amyloid as a seed that can further contaminate something that's already bad into something much worse – it's the trigger,” Bloom said. Just as importantly, the hypertoxic mixtures that are seeded by pyroglu beta-amyloid exist as small aggregates, called oligomers, rather than as much larger fibers found in the amyloid plaques that are a signature feature of the Alzheimer's brain.
And the trigger fires a “bullet,“ as Bloom puts it. The bullet is a protein called tau that is stimulated by beta-amyloid to form toxic “tangles” in the brain that play a major role in the onset and development of Alzheimer's. Using mice bred to have no tau genes, the researchers found that without the interaction of toxic beta-amyloids with tau, the Alzheimer's cascade cannot begin. The pathway by which pyroglu beta-amyloid induces the tau-dependent death of neurons is now the target of further investigation to understand this important step in the early development of Alzheimer's disease
“There are two matters of practical importance in our discovery,” Bloom said. “One, is the new insights we have as to how Alzheimer's might actually progress – the mechanisms which are important to understand if we are to try to prevent it from happening; and second, it provides a lead into how to design drugs that might prevent this kind of beta-amyloid from building up in the first place.”
Said study co-author Hans-Ulrich Demuth, a biochemist and chief scientific officer at Probiodrug, “This publication further adds significant evidence to our hypothesis about the critical role pyroglu beta-amyloid plays in the initiation of Alzheimer's Disease. For the first time we have found a clear link in the relationship between pyroglu beta-amyloid, oligomer formation and tau protein in neuronal toxicity.”
Bloom and his collaborators are now looking for other proteins that are needed for pyroglu beta-amyloid to become toxic. Any such proteins they discover are potential targets for the early diagnosis and/or treatment of Alzheimer's disease. (Source: EurekAlert! A service of AAAS and University of Virginia).
Get moving: Daily exercise may reduce Alzheimer's disease risk at any age
ST. PAUL, Minn. – Daily physical exercise may reduce the risk of Alzheimer's disease, even in people over the age of 80, according to a study published in the April 18, 2012, online issue of Neurology ®, the medical journal of the American Academy of Neurology.
“The study showed that not only exercise but also activities such as cooking, washing the dishes and cleaning are associated with a reduced risk of Alzheimer's disease,” said study author Aron S. Buchman, MD, with Rush University Medical Center in Chicago and a member of the American Academy of Neurology. “These results provide support for efforts to encourage physical activity in even very old people who might not be able to participate in formal exercise but can still benefit from a more active lifestyle.”
For the study, a group of 716 people with an average age of 82 wore an actigraph, a device that monitors activity, on their non-dominant wrist continuously for 10 days. All exercise and non-exercise was recorded. They also were given annual tests during the four-year study that measured memory and thinking abilities. During the study, 71 people developed Alzheimer's disease.
Participants also self-reported their physical and social activity. Buchman said this is the first study to use an objective measurement of physical activity in addition to self-reporting. “This is important because people may not be able to remember the details correctly,” he said.
The research found that people in the bottom 10 percent of daily physical activity were more than twice as likely to develop Alzheimer's disease as people in the top 10 percent of daily activity.
The study also showed that those people in the bottom 10 percent of intensity of physical activity were almost three times as likely to develop Alzheimer's disease as people in the top 10 percent of intensity of physical activity.
“Since the actigraph was attached to the wrist, activities like cooking, washing the dishes, playing cards and even moving a wheelchair with a person's arms were associated with a lower Alzheimer's risk,” said Michal Schnaider-Beeri, PhD, of Mount Sinai School of Medicine in New York in an accompanying editorial. “These are low-cost, easily accessible and side-effect free activities people can do at any age, including very old age, to possibly prevent Alzheimer's disease.” (Source: EurekAlert! A service of AAAS and American Academy of Neurology).
Alzheimer's precursor protein controls its own fate, study finds
Tampa, Fla. (April 10, 2012) – A research team led by the University of South Florida Department of Psychiatry & Behavioral Neurosciences has found that a fragment of the amyloid precursor protein (APP) -- known as sAPP-α and associated with Alzheimer's disease -- appears to regulate its own production. The finding may lead to ways to prevent or treat Alzheimer's disease by controlling the regulation of APP.
Their study is published online today in Nature Communications.
“The purpose of this study was to help better understand why, in most cases of Alzheimer's disease, the processing of APP becomes deregulated, which leads to the formation of protein deposits and neuron loss,” said study senior author Dr. Jun Tan, professor of psychiatry and the Robert A. Silver Chair, Rashid Laboratory for Developmental Neurobiology at the USF Silver Child Development Center. “The many risk factors for Alzheimer's disease can change the way APP is processed, and these changes appear to promote plaque formation and neuron loss.”
An estimated 30 million people worldwide and 5 million in the U.S. have Alzheimer's. With the aging of the “Baby Boom” generation, the prevalence of the debilitating disease is expected to increase dramatically in the U.S. in the coming years. Currently, there are no disease-modifying treatments to prevent, reverse or halt the progression of Alzheimer's disease, only medications that may improve symptoms for a short time.
“For the first time, we have direct evidence that a secreted portion of APP itself, so called 'sAPP-α,' acts as an essential stop-gap mechanism,” said the study's lead author Dr. Demian Obregon, a resident specializing in research in the Department of Psychiatry & Behavioral Neurosciences at USF Health. “Risk factors associated with Alzheimer's disease lead to a decline in sAPP-α levels, which results in excessive activity of a key enzyme in Aβ formation,”
In initial studies using cells, and in follow-up studies using mice genetically engineered to mimic Alzheimer's disease, the investigators found that the neutralization of sAPP-α leads to enhanced Aβ formation. This activity depended on sAPP-α's ability to associate with the APP-converting enzyme, BACE1. When this interaction was blocked, Aβ formation was restored.
The authors suggest that through monitoring and correcting low sAPP-α levels, or through enhancing its association with BACE, Alzheimer's disease may be prevented or treated. (Source: EurekAlert! A service of AAAS and University of South Florida [USF Health]).
A new gene thought to be the cause in early-onset forms of Alzheimer's disease
A new gene that causes early-onset of Alzheimer's disease has been discovered by the research team of Dominique Campion at the Insert unit 1079 “Genetics of cancer and neuropsychiatric diseases“ in Rouen. The research scientists showed that in the families of 5 of 14 patients suffering from the disease, mutations were detected on the gene SORL1. This gene regulates the production of a peptide involved in Alzheimer's disease. The results of this study have been published in the review Molecular Psychiatry issued April 3rd.
Precise genetic mutations have been seen to play a part in early-onset forms of Alzheimer's disease. However, there is a sub-population of patients in whom there is no mutation of these genes. So how can these patients, in whom there are no pre-established mutations, be suffering from early-onset Alzheimer's?
To reply to this question, the research team working under the leadership of Dominique Campion and Didier Hannequin (Inserm unit 1079 and Centre national de référence malades Alzheimer jeunes, University hospital Rouen), studied the genes from 130 families suffering from early-onset forms of Alzheimer's disease. These families were identified by 23 French hospital teams within the framework of the “Alzheimer Plan”. Of these families, 116 presented mutations on the already known genes. But in the 14 remaining families, there was no mutation at all observed on these genes.
A study of the genome of the 14 families using new whole DNA sequencing techniques showed evidence of mutations on a new SORL1 gene. The SORL1 gene is a coding gene for a protein involved in the production of the beta-amyloid peptide. This protein is known to affect the functioning of the brain cells (see insert).
Two of the identified mutations are responsible for an under-expression of SORL1, resulting in an increase in the production of the beta-amyloid peptide. “The mutations observed on SORL1 seem to contribute to the development of early-onset Alzheimer's disease. However, we still need to identify more clearly the way in which these mutations are transmitted on the SORL1 gene within families“ states Dominique Campion.
Alzheimer's disease is one of the main causes of dependency among the elderly. It results from neuron degradation in different areas of the brain. Its symptoms include increased alterations to memory, cognitive functions and behaviour disorders that lead to a progressive loss of independence.
Alzheimer's disease is characterized by the development of two types of lesion in the brain: amyloid plaques and neurofibrillary degenerescence. Amyloid plaques are caused by extracellular accumulation of a peptide, beta-amyloid peptide (Aβ) in specific areas of the brain. Neurofibrillary degenerescences are intraneuronal lesions caused by abnormal filamentary aggregation of a protein known as a Tau protein. (Source: EurekAlert! A service of AAAS and INSERM [Institut national de la santé et de la recherche médicale]).