Archive for the 'Alzheimers' Category
August 25th, 2008 -- Posted in Alzheimers, Mental Health |
Work could lead to new drugs for the common disease
MIT engineers report a new approach to identifying protein structures key to Alzheimer’s disease, an important step toward the development of new drugs that could prevent such structures from forming.
In the Aug. 22 issue of PLoS (Public Library of Science) Computational Biology, the researchers describe one such structure uncovered using a new computer-based technique.
Collin M. Stultz, the leader of the work and the W.M. Keck Associate Professor of Biomedical Engineering in the Department of Electrical Engineering and Computer Science, noted that the same general approach could also be applied to certain proteins associated with cancer.
Alzheimer’s disease is the most common form of dementia, affecting some five million Americans, according to the Alzheimer’s Association. And due to the growing elderly population, that number “is expected to reach a staggering 13.2 million by 2050,” said Stultz, who is also affiliated with the Harvard-MIT Division of Health Sciences and Technology (HST) and MIT’s Research Laboratory of Electronics.
Existing therapies, he continued, “do not adequately slow the rate of neurodegeneration in Alzheimer’s patients. As such, there is an urgent need to develop new treatments for Alzheimer’s dementia.”
Stultz’s approach to the problem combines his background in engineering and medicine (he holds a PhD and MD, and is a practicing cardiologist with appointments at Brigham and Women’s Hospital and the West Roxbury Veterans Administration Hospital). In his work, biochemical experiments inform a novel computer modeling technique aimed at better understanding one type of protein associated with the disease.
Alzheimer’s is characterized by two kinds of proteins — amyloid and tau — that aggregate in the brain. Stultz and co-author Austin Huang, an HST graduate student, have focused on determining the structure of tau.
But there’s a problem. “Tau is ‘natively unfolded,’ or floppy, so in solution it moves around a lot and can adopt many different structures,” Stultz said, much like the individual strands in a bowl of cooked spaghetti. Contrast that to the vast majority of other proteins, whose individual strands have similar structures, like the individual strands of uncooked spaghetti.
“With a ‘normal’ protein,” Stultz said, “you can measure the lengths of individual molecules and the average will be a pretty good description of any one.” Tau molecules, however, “are all over the place — they’re so diverse that it’s difficult to get one measurement that describes all of the possible structures.”
That complicates the hunt for specific tau structures associated with Alzheimer’s (not all tau is bad).
Stultz and Huang approached the problem as engineers, breaking it down into steps. Using a method they developed called Energy-minima Mapping and Weighting (EMW), they asked a computer to come up with all possible structures of tau that are consistent with an average set of experimental data.
“We generated lots and lots of structures for both normal tau and a mutant form” associated with an increased risk for Alzheimer’s, Stultz said. By comparing the two sets, the researchers found one structure that was more common in the mutant form — and therefore likely to “play a role in the pathologic process.” That structure, in turn, could then become the target for a new drug.
Stultz notes that the current work focused on one tau mutant associated with Alzheimer’s, but there are several others. So eventually he hopes to use EMW to create “a list of all types of suspect conformations for known tau mutants. Then, from that list, we can design drugs for each.”
This work was sponsored by a Jonathan Allen Junior Faculty Award.
Source: MIT News, Elizabeth A. Thomson (”http://web.mit.edu/newsoffice/2008/alzheimers-protein-0821.html“)
August 11th, 2008 -- Posted in Alzheimers, Mental Health |
For Jim Easton, a UCLA alumnus and longtime benefactor of the university, his $10 million donation to the Alzheimer’s Disease Center at UCLA’s Department of Neurology is truly a gift from the heart. It honors his mother, who died from the disease.
“My mother lived a long and productive life that ended in a devastating way,” Easton said. “She was involved in the beginning of my father’s small sporting goods manufacturing business and continued to work in the administrative and financial areas until the effects of Alzheimer’s caused her to retire.
“I hope my gift, along with donations from many others, will help make it possible for the talented scientists and physicians at UCLA to develop a cure and eventually prevent Alzheimer’s disease,” he said.
In recognition of Easton’s generosity, the center has been renamed the Mary S. Easton Center for Alzheimer’s Disease Research. Easton’s $10-million gift will support research by the newly established Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development, the principal research vehicle of the Easton Center.
A 1959 graduate of UCLA, Easton is chairman and chief executive officer of Jas. D. Easton Inc., a privately owned manufacturer of sports equipment, with headquarters in Van Nuys, Calif. He is a member of the U.S. Olympic Committee and the International Olympic Committee, for which he served as vice president from 2002 to 2006.
Easton has given generously to other areas at UCLA, including Intercollegiate Athletics, the Henry Samueli School of Engineering and Applied Science, and the Anderson School of Management.
Five inaugural projects have been chosen for support through the Easton Consortium. They reflect the most promising investigations in Alzheimer’s disease conducted by UCLA’s dedicated physicians and scientists. They include:
- Investigation of the molecular structure of the toxic protein that accumulates in the brain in Alzheimer’s disease.
- Studies of the molecular interactions that make the protein involved in Alzheimer’s toxic.
- Characterization of and intervention for Alzheimer’s in genetically engineered mouse models.
- Studies involving familial Alzheimer’s patients.
- Genetic studies and serial imaging of patients with Alzheimer’s.
“I am truly grateful for Jim’s commitment to accelerating leading-edge research to develop new treatment approaches and prevention strategies for Alzheimer’s disease,” said Dr. Jeffrey Cummings, UCLA professor of neurology and director of the Easton Center.
Founded in 1991, UCLA’s Alzheimer’s research center conducts research and provides care relevant to normal aging, mild cognitive impairment, Alzheimer’s disease and other causes of late-onset cognitive decline.
A formal dedication ceremony for the Easton Center will take place this fall.
The Mary S. Easton Center for Alzheimer’s Disease Research is part of the UCLA Department of Neurology, which encompasses more than a dozen research, clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer’s disease and other dementias, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranked No. 1 in 2005 and 2006 among its peers nationwide in National Institutes of Health funding. For more information, visit
http://neurology.medsch.ucla.edu/.
July 22nd, 2008 -- Posted in Alzheimers, Mental Health |
Every aging baby boomer listens for the footsteps of Alzheimer’s, and for good reason: It’s estimated that 10 million American boomers will develop the disease. The need to develop preventative strategies, ideally long before Alzheimer’s destructive, clinical symptoms appear, is critical.
In furthering the steps toward that goal, UCLA associate professor of neurology John Ringman and his colleagues confirm in the current issue of the journal Neurology that during Alzheimer’s earliest stages, levels of specific proteins in the blood and spinal fluid begin to drop as the disease progresses, making them potentially useful as biomarkers to identify and track progression long before symptoms appear.
Identifying patients at the clinically “silent” stage is a prerequisite for advancing the strategies needed to prevent the symptoms from appearing. The hope is that one day, screening for such biomarkers could take its place beside such routine tests as colonoscopies and mammograms as another common tool of preventive medicine.
Familial Alzheimer’s and sporadic Alzheimer’s are two of the basic types of the disease. The majority of Alzheimer’s cases are sporadic and late-onset, developing after the age of 65; the causes of this disease type are not completely understood. Familial Alzheimer’s (FAD) is a rare form of the disease caused by certain gene mutations that affects less than 2 percent of Alzheimer’s patients. FAD is early-onset, meaning the disease develops before age 65, and it is inherited; all offspring in the same generation have a 50-50 chance of developing FAD if one of their parents had it. The markers the researchers tracked came from people with the FAD mutations.
“Since we knew that 50 percent of first-degree relatives will inherit the same rare mutations, we were able to study the biochemical changes occurring in the cerebrospinal fluid and blood as long as 30 years before the subjects were likely to develop the disease themselves,” said Ringman, who is the assistant director of the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA. “This allowed us to identify markers that might be used to diagnose the disease prior to the development of overt symptoms, and also tells us a lot about the chain of events that cause the disease.”
The study looked at several proteins that exist in the cerebrospinal fluid and plasma in 21 FAD mutation carriers and compared them to noncarriers. Knowing that the extracellular plaques characteristic of Alzheimer’s that form in the brain consist largely of a fibrous beta-amyloid protein called AB42, the researchers looked at that protein and found that it was elevated in the plasma of FAD mutation carriers, appearing long before the development of obvious dementia. The level then appears to drop as the disease progresses. In addition, the researchers showed that the ratio of AB42 to another protein, AB40, was reduced in the cerebrospinal fluid of FAD mutation carriers and, further, that the levels of two other proteins, called t-tau and p-tau181, were elevated prior to overt symptoms.
“These results are worth highlighting because of the implications for Alzheimer’s prevention research,” Ringman said. “The presence of cerebrospinal fluid biomarkers of Alzheimer’s disease prior to any clinical symptoms suggests the pathology of Alzheimer’s precedes the clinical symptoms and further demonstrates that it may be possible to detect those changes prior to the appearance of cognitive dysfunction.”
The use of subjects at risk for autosomal dominant Alzheimer’s disease is both a strength and a weakness of the study, Ringman said. Using research subjects that are known to have a predisposition to Alzheimer’s calls for caution. On the one hand, he said, “this population can be genetically defined so we can predict whether they will or will not develop the disease in the future with a high degree of certainty. However, these mutations are very rare, and some findings in this rare form of Alzheimer’s disease may not generalize to more typical late-onset Alzheimer’s disease.”
Nevertheless, he said, since the pathology of FAD is essentially identical to that of sporadic Alzheimer’s, it is plausible that the preclinical changes in these proteins are common to all forms of the disease and bear more scrutiny.
The study was supported by several sources, including the Shirley and Jack Goldberg Trust, the Brotman Foundation of California, the National Institute on Aging, a grant from the Alzheimer’s Disease Research Center of California, and the Sidell Kagan Foundation. Other authors include S.G. Younkin, D. Pratico, W. Seltzer, G.M. Cole, D.H. Geschwind, Y. Rodriguez, B. Schaffer, J. Fein, S. Sokolow, E.R. Rosario, K.H. Gylys, A. Varpetian, L.D. Medina and J.L. Cummings. The authors report no conflicts of interest.
The Mary S. Easton Center for Alzheimer’s Disease Research at UCLA is a comprehensive research and clinical program for individuals with memory complaints, Alzheimer’s disease and related conditions. It is part of the UCLA Department of Neurology, which encompasses more than a dozen research, clinical and teaching programs. The department ranked No. 1 in 2005 and 2006 among its peers nationwide in National Institutes of Health funding.
Source: UCLA Newsroom, Mark Wheeler (http://www.newsroom.ucla.edu/portal/ucla/an-id-for-alzheimer-s-53281.aspx)
July 21st, 2008 -- Posted in Alzheimers, Brain Food, Mental Health |
MIT brain researchers have developed a “cocktail” of dietary supplements, now in human clinical trials, that holds promise for the treatment of Alzheimer’s disease.
For years, doctors have encouraged people to consume foods such as fish that are rich in omega-3 fatty acids because they appear to improve memory and other brain functions.
The MIT research suggests that a cocktail treatment of omega-3 fatty acids and two other compounds normally present in the blood, could delay the cognitive decline seen in Alzheimer’s disease, which afflicts an estimated 4 million to 5 million Americans.
“It’s been enormously frustrating to have so little to offer people that have (Alzheimer’s) disease,” said Richard Wurtman, the Cecil H. Green Distinguished Professor of Neuropharmacology at MIT, who led the research team. The study appears in the May 9 issue of Brain Research.
Wurtman will present the research at the International Academy of Nutrition and Aging 2006 Symposium on Nutrition and Alzheimer’s Disease/Cognitive Decline in Chicago on Tuesday, May 2.
The three compounds in the treatment cocktail — omega-3 fatty acids, uridine and choline — are all needed by brain neurons to make phospholipids, the primary component of cell membranes.
After adding those supplements to the diets of gerbils, the researchers observed a dramatic increase in the amount of membranes that form brain cell synapses, where messages between cells are relayed. Damage in brain synapses is believed to cause the dementia that characterizes Alzheimer’s disease.
If the successful results obtained in gerbils can be duplicated in the ongoing human trials, the new treatment could offer perhaps not a cure but a long-term Alzheimer’s treatment similar to what L-dopa, a dopamine precursor, does for Parkinson’s patients, said Wurtman, a professor in the Department of Brain and Cognitive Sciences.
“It doesn’t cure Parkinson’s, but what it does do is to help replace something that’s missing. It’s not permanent, but it has had an enormous impact on people who have Parkinson’s,” he said.
The new potential treatment offers a different approach from the traditional tactic of targeting the amyloid plaques and tangles that develop in the brains of Alzheimer’s patients. Until recently, most researchers believed these plaques and tangles caused the cognitive decline. But the failure of this hypothesis to lead to an effective treatment for Alzheimer’s disease has caused some scientists to theorize that, though the plaques and tangles are always associated with the disease, they may not be the main cause of the dementia, nor the best target for treating it.
Instead, the new research focuses on brain synapses, where neurotransmitters such as dopamine, acetylcholine, serotonin and glutamate carry messages from presynaptic neurons to receptors in the membranes of postsynaptic neurons. In Alzheimer’s patients, synapses in the cortex and hippocampus, which are involved in learning and memory, are damaged.
After the dietary supplements were given, the researchers detected a large increase in the levels of specific brain proteins known to be concentrated within synapses, indicating that more synaptic membranes had formed, Wurtman said. Synaptic membrane protein levels rose if the gerbils were given either omega-3 fatty acids or uridine plus choline. However, the most dramatic upsurge was observed in gerbils fed all three compounds.
“To my knowledge, this is the first concrete explanation for the behavioral effects of taking omega-3 fatty acids,” said Wurtman.
Choline can be found in meats, nuts and eggs, and omega-3 fatty acids are found in a variety of sources, including fish, eggs, flaxseed and meat from grass-fed animals. Uridine, which is found in RNA and produced by the liver and kidney, is not obtained from the diet. However, uridine is found in human breast milk, which is a good indication that supplementary uridine is safe for humans to consume, Wurtman said.
Recent studies by the researchers at MIT, and by scientists at Cambridge University in England, showed that either uridine or omega-3 fatty acids can promote the growth of neurites, which are small outgrowths of neuronal cell membranes. That further supports the hypothesis that omega-3 fatty acids increase synaptic membrane formation, said Wurtman.
Alzheimer’s patients in the clinical trials, which will involve multiple medical centers, are being given a drink that contains the compounds under study, or a taste-matched placebo.
“If it works as well on the brains of people with Alzheimer’s disease as it does in laboratory animals, I think there will be a lot of interest,” Wurtman said.
Other authors on the paper are Ismail Ulus, Mehmet Cansev, Carol Watkins, Lei Wang and George Marzloff of MIT’s Department of Brain and Cognitive Sciences. Ulus and Cansev also work at the Uludag University School of Medicine in Turkey.
The research was supported by the National Institutes of Health, the Center for Brain Sciences and Metabolism Charitable Trust and the Turkish Academy of Sciences.
Source: MIT News (http://web.mit.edu/newsoffice/2006/alzheimers.html)
July 21st, 2008 -- Posted in Alzheimers, Mental Health |
A type of omega-3 fatty acid may slow the growth of two brain lesions that are hallmarks of Alzheimer’s disease, UC Irvine scientists have discovered. The finding suggests that diets rich in docosahexaenoic acid (DHA) can help prevent the development of Alzheimer’s disease later in life.
This study with genetically modified mice is the first to show that DHA, an omega-3 fatty acid, can slow the accumulation of tau, a protein that leads to the development of neurofibrillary tangles. Such tangles are one of two signature brain lesions of Alzheimer’s disease. DHA also was found to reduce levels of the protein beta amyloid, which can clump in the brain and form plaques, the other Alzheimer’s lesion.
Previous studies have shown that DHA may have therapeutic value for Alzheimer’s patients, but this research is among the first to show that it may delay the onset of the disease. DHA is found in fish, eggs, organ meats, micro-algae, fortified foods and food supplements.
“We are greatly excited by these results, which show us that simple changes in diet can positively alter the way the brain works and lead to protection from Alzheimer’s disease pathology,” said Frank LaFerla, professor of neurobiology and behavior and co-author of the study.
This research appears in the April 18 issue of The Journal of Neuroscience.
LaFerla and his research team studied the effects of DHA in mice bred to develop the plaques and tangles associated with Alzheimer’s disease. Mice in the control group were given food that mimics a typical American diet, with the ratio of omega-6 fatty acids to omega-3 fatty acids being 10:1. Studies indicate that a proper ratio is important to maintain health, with the ideal being 3:1 to 5:1. Typical Western diets contain unhealthy ratios ranging from 10:1 to 30:1. Omega-6 fatty acids are found in corn, peanut and sunflower oils.
Mice in three test groups were given food with a 1:1 ratio of omega-6 fatty acids to omega-3 fatty acids. One of these groups received supplemental DHA only, and two groups received DHA plus additional omega-6 fatty acids. After three months, mice in all of the test groups had lower levels of beta amyloid and tau than mice in the control group, but at nine months, only mice on the DHA diet had lower levels of both proteins. These results suggest that DHA works better on its own than when paired with omega-6 fatty acids.
The scientists also determined the mechanism by which DHA leads to lower levels of beta amyloid. DHA, they found, leads to lower levels of presenilin, an enzyme responsible for cutting beta amyloid from its parent, the amyloid precursor protein. Without presenilin, beta amyloid cannot be generated. When clumped into plaques, beta amyloid disrupts communication between cells and leads to symptoms of Alzheimer’s disease.
This latest study adds to growing evidence that diet and lifestyle changes may reduce the risk of developing Alzheimer’s disease. LaFerla and his team have previously shown that short but repeated learning sessions can slow the physical progression of Alzheimer’s in mice, suggesting that the elderly can delay onset of the disease by keeping their minds active. The team also found that stress hormones appear to rapidly exacerbate the formation of plaques and tangles, suggesting that managing stress could slow the progression of Alzheimer’s.
“Combined with mental stimulation, exercise, other dietary intakes, and avoiding stress and smoking, we believe that people can significantly improve their odds against this disease,” said Kim Green, scientist and lead author on the DHA, learning and stress studies.
Alzheimer’s is a progressive neurodegenerative disorder that affects more than 4.5 million adults in the United States. With an aging population, that number could approach 20 million by 2050. Five percent of people older than 65 have Alzheimer’s, and up to one-half of people are affected by age 80.
UCI scientists Hilda Martinez-Coria and Hasan Khashwji, along with Martek Biosciences Corp. researchers Eileen Hall, Karin Yurko-Mauro and Lorie Ellis worked on this study.
Martek funded the study, and two clinical trials evaluating DHA are under way. The first trial, sponsored by Martek and the National Institute on Aging and conducted by the Alzheimer’s Disease Cooperative Study, is examining the effects of DHA in slowing the progression of cognitive and functional decline in patients with mild to moderate Alzheimer’s disease. The second trial, also sponsored by Martek, is evaluating the effects of DHA on age-related cognitive decline in healthy, older adults with mild memory complaints. For more information, visit www.clinicaltrials.gov.
About the University of California, Irvine: The University of California, Irvine is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 25,000 undergraduate and graduate students and about 1,800 faculty members. The second-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.7 billion. For more UCI news, visit www.today.uci.edu.
Source: Today @ UCI (http://today.uci.edu/news/release_detail.asp?key=1594)
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