Archive for the ‘Alzheimer’s disease’ Category
Insulin May Help Treat Alzheimer’s
Last Updated on Wednesday, 14 September 2011 01:54 Written by admin Wednesday, 14 September 2011 01:54
Researchers are investigating insulin as a possible treatment for Alzheimer’s disease, and in a preliminary study, the results look promising.A study in the journal Archives of Neurology suggests that intranasal insulin – that is, delivered through the nose – may help with cognition and functioning in patients who have both mild and more severe dementia.It’s premature to think of this as a treatment; the study only looked at 104 people, and needs to be repeated in much larger groups before it can be deemed effective. But it sets the stage for broader clinical trials.Recent research has suggested that insulin plays an important role in a number of brain functions, in addition to regulating blood sugar. Insulin promotes cell repair and cell genesis, so the thinking is that it could actually modify the course of Alzheimer’s disease, says lead study author Suzanne Craft, professor of psychiatry at VA Puget Sound and University of Washington.It also appears to protect against the toxic effects of beta-amyloid, the protein involved in the brain plaques associated with dementia. Insulin also prevents the formation of the toxic form of tau, a biomarker found in the cerebrospinal fluid of Alzheimers’ patients, Craft said.”What we saw was that for the insulin-treated patients, the ones who had improvement in memory and function had improvement in spinal fluid biomarkers,” she said.The goal of this study was to supplement and normalize the insulin levels in the brain without affecting levels in the rest of the body. This was done with a device that was designed to deliver insulin through the nose to the brain without getting too much into the blood.Researchers tested patients who had either early Alzheimer’s or mild cognitive impairment, a team for the early stages of dementia.Patients treated with insulin were able to remember information over a period of time better than those who got placebo; in fact, performance improved 20%. They also showed an enhancement in brain glucose metabolism in some areas; those who received placebo tended to show a decline.Alzheimer’s patients in the insulin group benefited more in terms of daily function than those with mild cognitive impairment, but by definition mild cognitive impairment does not greatly impair daily functioning.The treatment had the mild side effects of occasional mild headache and runny nose, but had a good safety profile generally, Craft said.In patients with mild cognitive impairment, researchers observed improvement in daily function and general cognitive abilities.But researchers don’t know what would be the optimal dosing and schedule of intranasal insulin for treating dementia; that is still an open question.So what does this mean for diabetics who already give themselves daily injections of insulin to manage their condition? Researchers don’t yet understand how much of that insulin is actually getting into the brain, Craft said; and if you’re not diabetic, having high levels of insulin in the blood is probably not good in the long run, so no one should experiment with this at home. Diabetes is a known risk factor for Alzheimer’s, but there are a lot of unanswered questions about that connection.
Source: http://www.kxly.com/health/29172695/detail.html
Posted under Alzheimer's disease, Cell Analysis, Discoveries, Innovations and Patents, Genetics & Pharmacogenetics, Press Releases, R & D, Reports, Research Projects | Comments Off
Coffee buzz protects brain from Alzheimer’s
Last Updated on Thursday, 30 June 2011 11:00 Written by admin Thursday, 30 June 2011 11:00
For years we’ve been told that caffeinated coffee was bad for us. It’s unhealthy and addictive, doctors warned. But as vindication for all who stuck by their energizing elixir, a new study shows that guzzling caffeinated coffee may actually be good for our brains. In fact, it may help keep Alzheimer’s at bay.
The study, which was published early online in the Journal of Alzheimer’s Disease, was in mice whose DNA had been tweaked to contain a human Alzheimer’s gene. Just like humans with familial Alzheimer’s, these mice become increasingly forgetful as they age.
Amazingly, the equivalent of four to five cups of caffeinated coffee every few days led to much improved memories in the Alzheimer’s mice, says study co-author Gary Arendash, a scientist at the Florida Alzheimer’s Disease Research Center in Tampa.
Earlier research by Arendash and his colleagues showed that caffeine could at least partially block the production of beta amyloid, the sticky protein that clogs the brains of Alzheimer’s patients. They also found that a substance called granulocyte-colony stimulating factor, or GCSF, sparked the production of new axons, the communication cables that link nerve cells together, as well as new nerve cells themselves.
What’s really interesting is that caffeinated coffee — but not decaf — boosted the production of GCSF.
For the new study, Arendash and his colleagues “treated” healthy mice and Alzheimer’s mice with either caffeinated or decaffeinated coffee. Then the researchers ran a test to see if either beverage led to better memories.
The test they used mimics one that is given to humans to diagnose Alzheimer’s. In that test, people are given a bag of objects to look through (we’ll call that Bag A). And then they’re shown another bag of objects (Bag B). Later on, they’re asked to remember what was in Bag A.
Studies have shown that people with Alzheimer’s have a tough time remembering what was in Bag A because the distraction of looking through the objects from Bag B gets in the way of storing the contents of A in their long term memories. That’s generally not a problem for people with healthy brains.
The two part mouse test involved water mazes. The mice has to find — and remember — the location of a submerged platform in a tub of water that is deep enough that they need to swim till they find the platform.
After they find the platform in one tub, they’re moved to another tub where they have to find yet another platform. Mice with Alzheimer’s generally have a tough time remembering the location of the first platform when they’re placed in the original tub. But in Arendash’s study, Alzheimer’s mice that got caffeinated coffee had memories that were just as good as those of normal mice.
Lest you dismiss this study because it’s just in rodents, Arendash says he’s got new data in humans. That data is still being analyzed, he says, but so far it looks like caffeinated coffee has the same impact in people as it does in mice.
Source: http://bodyodd.msnbc.msn.com/_news/2011/06/28/6968218-coffee-buzz-protects-brain-from-alzheimers
Posted under Alzheimer's disease, Cell Analysis, Discoveries, Innovations and Patents, North America, R & D, Reports, Research Projects, USA and Canada | Comments Off
Protein ‘helps predict Alzheimer’s risk’
Last Updated on Thursday, 23 June 2011 12:53 Written by admin Thursday, 23 June 2011 12:53
A protein in spinal fluid could be used to predict the risk of developing Alzheimer’s disease, according to German researchers.
Patients with high levels of the chemical – soluble amyloid precursor protein beta – were more likely to develop the disease, they found.
Doctors said in the journal Neurology this was more precise than other tests.
Alzheimer’s Research UK said early diagnosis was a key goal, and the study represented a potential new lead.
Doctors analysed samples of spinal fluid from 58 patients with mild cognitive impairment, a memory-loss condition which can lead to Alzheimer’s.
The patients were followed for three years. Around a third developed Alzheimer’s.
Those who developed the illness had, on average, 1,200 nanograms/ml of the protein in the spinal fluid at the start of the study.
Those who did not started with just 932 nanograms/ml.
Beta amyloid proteins have already been implicated in Alzheimer’s itself, but not as a “predictor” of the disease.
The researchers said that a combination of soluble amyloid precursor protein beta, defective tau proteins, which are involved in the structure of brain cells, and a patient’s age was 80% accurate in predicting the onset of the disease.
Early diagnosis crucial
There is no cure for Alzheimer’s disease. If a treatment is developed, it is thought that it would need to be delivered early, before any permanent damage was done.
Dr Robert Perneczky, from the Technical University Munich, said: “Being able to identify who will develop Alzheimer’s disease very early in the process will be crucial in the future.
“Once we have treatments that could prevent Alzheimer’s disease, we could begin to treat very early and hopefully prevent the loss of memory and thinking skills that occurs with this devastating disease.”
More than 800,000 people have dementia in the UK, and that figure is expected to rise as populations get older.
Rebecca Wood, chief executive of Alzheimer’s Research UK, said: “The ability to diagnose Alzheimer’s early is a key goal for doctors and researchers. This small study provides a potential new lead to follow up.
“We will need to see larger trials before we can know how accurate this method could be as a diagnostic test. It will also be important to see how measurements of these proteins compare to those found in healthy people.”
Source: http://www.bbc.co.uk/news/health-13875984
Posted under Alzheimer's disease, Discoveries, Innovations and Patents, Europe, Europe, Medicinal Chemistry, R & D, Reports | Comments Off
Five New Alzheimer’s Genes Double Total as Doctors Unravel Disease Cause
Last Updated on Monday, 4 April 2011 10:01 Written by admin Monday, 4 April 2011 10:01
Five new genes have been definitively linked to Alzheimer’s disease, doubling the total confirmed by scientists and opening new areas for research into an illness that affects 35 million people globally.
The genetic pathways were reported in two studies involving more than 50,000 people worldwide. Some of the connections found involve systems that control inflammation and cholesterol in the brain, while others affect how brain cells remove toxic proteins, the researchers wrote in reports published yesterday in the journal Nature Genetics.
The newest confirmed genes raise risks for Alzheimer’s by 15 percent or less, not strong enough to be used as a marker for the disease, researchers said. Their worth is in suggesting new areas of study that may one day help speed creation of therapies for a malady that progressively destroys brain cells and makes it difficult for people to think, remember and function.
“We are beginning to piece together the jigsaw and gain new understanding,” said lead researcher Julie Williams, a professor from Cardiff University’s Centre for Neuropsychiatric Genetics and Genomics in Wales. “We still have a long way to go, but the jigsaw is beginning to come together.”
Inflammation, cholesterol and the build-up of beta amyloid protein have long been thought to play a critical role in the degradation of nerve cells in the brain, the researchers said. If treatments can prevent the detrimental effects of the genes, doctors may be able to one day reduce the number of people with Alzheimer’s disease, Williams said.
Important Combinations
Researchers are trying to determine which gene variations, and which combinations, are most important. Identifying how genes work together may speed studies of experimental drugs, said David Bennett, director of the Alzheimer’s Disease Center at Rush University Medical Center in Chicago, in a statement.
“These findings add key information needed to understand the causes of Alzheimer’s disease and should help in discovering approaches to its treatment and prevention,” Bennett said.
The U.S. National Institute on Aging helped fund the studies, which used information gleaned from five different groups, including the Rush Religious Orders Study, to analyze the genetic makeup of more than 54,000 people.
Alzheimer’s is characterized by the formation of plaque in the brain from amyloid and tau proteins. Scientists don’t know why the proteins accumulate or become twisted, whether they cause the illness or if they are an end-product resulting from a different process altogether.
“We know from our studies there are going to be dozens of these genes that will be significant when the collective data is analyzed,” said Rudolph Tanzi, professor of neurology at Harvard Medical School in Boston, and an author of one paper.
Most Exciting
While the combined genes point at several pathways that may play a role in Alzheimer’s disease, Tanzi says he is most excited about CD33, a gene he discovered that is tied to the brain’s primitive innate immune system. In some cases, it might not be eliminating as much beta amyloid as it should. In others, it may be too active and trigger inflammation, he said in a telephone interview.
“Once we figure out what’s going on, CD33 will be a good target because it sits on the cell surface,” he said. “But it will be at least 10 years before we could turn these targets into drugs,” said Tanzi, who is also director of the genetics and aging research unit at Massachusetts General Hospital’s Institute for Neurodegenerative disease.
The number of Alzheimer’s sufferers is predicted to reach 115.4 million by 2050, according to a 2009 report from Alzheimer’s Disease International.
Inevitable Deterioration
No treatment is yet available to slow or stop deterioration of the brain in patients with Alzheimer’s. Drugs aiming to slow the symptoms include Namenda from New York-based Forest Laboratories Inc. (FRX), and Aricept from New York-based Pfizer Inc. (PFE) and Tokyo-based Eisai Co.
As much as 80 percent of a person’s chance of developing Alzheimer’s is inherited, doctors say. About 400 genes have been identified that scientists believe may play a role in the condition, named for the German doctor Alois Alzheimer who described it in 1906.
The greatest inherited risk comes from the APOE gene, discovered in 1993 by a team led by Allen Roses, now director of the Deane Drug Discovery Institute at Duke University Medical Center in Durham, North Carolina. A person who inherits that gene from one parent has a 400 percent increased risk of getting the disease.
Source: http://www.bloomberg.com/news/2011-04-04/five-new-alzheimer-s-genes-double-total-in-new-push-for-cure.html
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Iona Chemistry Professor Researches Cure For ALZ
Last Updated on Monday, 20 December 2010 03:17 Written by Editor Monday, 20 December 2010 03:17
New Rochelle, NY – Do curry spice, wine and apple skins hold the answer for finding a cure for Alzheimer’s disease, Parkinson’s disease and other neurological disorders?
The results of a laboratory research project, recently published in the Journal of Neurochemistry, show that a chemical compound derived from these natural products may be used in neutralizing the toxic effects of chemicals associated with some debilitating and life-threatening neurological diseases.
The findings are the result of a four-year study undertaken by Terrence Gavin, Ph.D., a chemistry professor at Iona College and Richard M. LoPachin, Ph.D, a neurochemist and director of research in the Department of Anesthesiology at Montefiore Medical Center and the Albert Einstein College of Medicine.
In lab experiments it was found that the compound, called 2-ACP, completely protects nerve cells from the harmful effects of type-2 alkenes. There is growing evidence that exposure to type 2-alkenes, which are found in the smoke inhaled from cigarettes, the exhaust of automobiles and even in French fried potatoes, can increase the chances of developing Alzheimer’s and otherneurological conditions. In addition, studies
have shown type-2 alkenes are being produced within the nerve endings during the disease process that presumably initiates Alzheimer’s.
Dr. Gavin said: “The research Dr. LoPachin and I undertook is promising because chemical compounds extracted from curry spice, red wine and apple skins, which are widely used natural products, have already been clinically demonstrated to have neuroprotective properties. This suggests it would be safe and effective to treat humans with the 2-ACP compound.”
He added: “But, these molecular findings worked in laboratory cultures. We now need to confirm the effects of 2-ACP in animal studies. That will be the focus of our efforts in the coming months.”
In addition, Dr. Gavin and some of his students
at Iona will be looking for new compounds that will be as good or better than 2-ACP in combating the effects of type 2-alkenes. “Our goal is to have new compounds ready for testing in six months. This is a very exciting scientific exploration,” Dr. Gavin stated.
Dr. Gavin has been a chemistry professor at Iona since 1982. He holds a doctoral degree in chemistry from the State University of New York at Stony Brook and attended the State University of New York at New Paltz where he earned a B.A. degree. He and his family live in New Paltz.
Source: westchester.com
Posted under Alzheimer's disease, Clinical Trials, Discoveries, Innovations and Patents, Drug Development, Medicinal Chemistry, Natural Products, North America, Reports, Research Projects, USA and Canada | Comments Off
Screen for molecules that inhibit formation of A-beta oligomers
Last Updated on Thursday, 5 August 2010 02:00 Written by Editor Thursday, 5 August 2010 02:00
Alzheimer’s disease (AD) is a devastating neurological disorder characterized by the deposition of aggregated proteins in the brain in the form of extracellular beta-amyloid in senile plaques and intracellular tau in neurofibrillary tangles. A current approach towards treatment of Alzheimer’s disease is by using inhibitors of amyloid beta aggregation. Current screening protocols for inhibitors of amyloid beta aggregation generally involve first using assays for fibers, e.g, thioflavin T binding to detect inhibition of fiber formation or fiber disassembly, and the compounds uncovered in these screens are then examined for effects on oligomer formation. This approach for screening compounds having amyloid beta aggregation inhibition properties is an indirect one, but is used because oligomers do not bind thioflavin T and there is no easy assay for their appearance. A compound which only inhibits oligomer formation, but does not inhibit protective fiber growth would never be detected by this indirect approach. The present UIC invention overcomes these deficiencies and provides an easy and direct assay in yeast for high-throughput screening of compounds that can inhibit amyloid-beta oligomer formation but does not inhibit protective fiber growth.
Description/Details
The present UIC invention is directed towards a yeast high-throughput screen for detecting compounds that inhibit amyloid-beta aggregation. It also provides a yeast in vivo assay for amyloid-beta aggregation. The assay involves replacing the N-terminus of the translational release factor, Sup35, with Abeta-42mer, and examining the activity of said construct in an ade1-14 yeast strain in which the normal Sup35 gene was deleted, and inhibition of release factor translation termination activity of the fusion construct can be assayed for growth on –Ade medium.
Applications
Screening for compounds that inhibit amyloid-beta oligomer formation
Benefits
• Easily detects compounds that inhibit amyloid-beta oligomer formation but do not inhibit protective fiber growth Selects compounds with more “drug-like” properties (e.g., membrane permeability and cytotoxicity effects) compared to biochemical HTS screens, Clean read-out against a null background in a heterologous, yet eukaryotic environment, compared to mammalian cells, Self-renewal system, Simple handling, Fast discrimination of real hits from false positives, Inexpensive culture conditions
source: otm.illinois.edu
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Neuronetrix’ COGNISIONâ„¢ System
Last Updated on Saturday, 24 July 2010 04:09 Written by admin Tuesday, 6 July 2010 02:11
Alzheimer’s disease is a chronic neurodegenerative disease of the brain which afflicts roughly 5 million individuals in the United States. Approximately 10% of those over 65 and 50% of those over 85 will die as a result of Alzheimer’s disease.
Even with several therapies available to treat Alzheimer’s disease, there still is a significant gap between the onset of the disease and point at which treatment actually begins. This treatment gap is directly tied to the challenges in diagnosing the disease early, before the significant loss of memory, cognition, and activities of daily living. Patients, doctors, caregivers, and the pharmaceutical industry, are looking for and demanding a solution to this problem.
Neuronetrix’ COGNISIONâ„¢ System will, for the first time, directly detect the abnormal cognitive effects of Alzheimer’s disease! This will facilitate an earlier and more accurate diagnosis than is currently available. Physicians will use the COGNISIONâ„¢ test to determine which patients would benefit from the available drug treatments. The system can also be used to monitor the efficacy of the prescribed therapy.
With the aging of America and the proliferation of new Alzheimer’s therapies, the market for Alzheimer’s screening could approach several billion dollars per year in the United States alone.
Following the validation of the COGNISION™ System for Alzheimer’s disease, Neuronetrix will expand into other neurodiagnostic markets such as ADHD, dyslexia, and depression.
http://www.neuronetrix.com/
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New compounds may help develop drugs for degenerative nerve diseases
Last Updated on Wednesday, 12 May 2010 12:52 Written by Editor Wednesday, 12 May 2010 12:52
Scientists at Duke University Medical Centre have discovered certain compounds that could lead to promising new drugs for degenerative nerve diseases, such as Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.
Misfolded proteins in nerve cells (neurons) are a common factor in all of these diseases.
These new compounds improve a cell’s ability to properly “fold†proteins.
It activates a master regulator to increase the supply of “protein chaperone†molecules that help fold proteins properly.
The scientists further explored one of the candidate molecules to activate the master regulator of chaperone gene expression, Heat Shock Factor 1 (HSF1), to learn whether it would work in model systems of Huntington’s disease, a devastating neurodegenerative disease of protein misfolding.
They were able to show that the molecule stimulated protein chaperones in cells and in an animal system.
The damage to early-state rat neurons was much lower in cells pre-treated with the HSF1 activator, and damage to the neurons of fruit flies that had a Huntington’s-like disorder was also greatly reduced.
The study provides a new approach to address the root cause of these diseases – protein misfolding.
“The advantage of our screen is that it identifies molecules that can elevate the levels of chaperones without inducing cellular stress and that don’t inhibit a key protein chaperone called Hsp90 that is needed for cells to function normally,†said senior author Dennis J. Thiele, Ph.D., Professor of Pharmacology and Cancer Biology.
“We found a creative way to identify new molecules that can activate the body’s natural protein folding machinery,†he added.
Lead author Daniel Neef, Ph.D., says they used genetically altered yeast to find compounds that might aid chaperone development.
The study appears online in PLoS Biology. (ANI)
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New class of brain-protecting drugs emerging
Last Updated on Wednesday, 12 May 2010 12:51 Written by Editor Wednesday, 12 May 2010 12:51
Researchers have identified a compound that mimics one of the brain’s own growth factors and can protect brain cells against damage in several animal models of neurological disease.
7,8-dihydroxyflavone is a member of the flavonoid family of chemicals, which are abundant in fruits and vegetables. The compound’s selective effects suggest that it could be the founder of a new class of brain-protecting drugs.
The results were published online this week in the Proceedings of the National Academy of Sciences.
Investigators at Emory University School of Medicine, led by Keqiang Ye, PhD, associate professor of pathology and laboratory medicine, were searching for a way to mimic a protein found in the brain called BDNF (brain-derived neurotrophic factor).
“BDNF has been studied extensively for its ability to protect neurons vulnerable to degeneration in several diseases, such as ALS, Parkinson’s and Alzheimer’s disease,” Ye says. “The trouble with BDNF is one of delivery. It’s a protein, so it can’t cross the blood-brain barrier and degrades quickly.”
Working with Ye, postdoctoral fellow Sung-Wuk Jang sifted through a library of chemicals to find those that could stimulate one of the proteins on the surfaces of neurons that BDNF binds to. They could show that 7,8-dihydroxyflavone sends survival signals to brain cells by pulling together two TrkB receiver-dish molecules, just like BDNF does.
Moreover, it is active in the brain when injected into the body cavity, meaning that it can cross the blood-brain barrier. Ye says many experimental “neuroprotectant” drugs have been unsuccessful in clinical trials for diseases such as stroke and Parkinson’s over the last decade.
“What’s different is this is a new pathway, offering us new opportunities,” he says. “This is the first molecule we’ve found that specifically triggers TrkB.”
7,8-dihydroxyflavone could partially prevent the death of neurons in experimental models of three neurological diseases:
- Seizure: Mice treated with the stimulant kainic acid
- Stroke: Loss of blood flow induced in mice by blocking a cerebral artery
- Parkinson’s disease: Mice treated with a toxin that kills the same neurons affected by Parkinson’s
To show that the effects of 7,8-dihydroxyflavone depended on TrkB, the authors used mice with a modified TrkB gene, which makes their neurons vulnerable to a chemical that is not otherwise toxic. That chemical could inhibit the effects of 7,8-dihydroxyflavone.
7,8-dihydroxyflavone is a member of a family of antioxidant compounds naturally found in foods ranging from cherries to soybeans. Tests in animals indicate that the compound has low chronic toxicity, Ye says. In clinical trials, BDNF itself can have side effects such as sensory alterations, weight loss or nausea.
“It is likely that many people take in small amounts of 7,8-dihydroxyflavone in their diets,” Ye says. “But drinking green tea or eating apples doesn’t give you enough for a sustained effect.”
In the initial screening process, several flavonoid compounds had similar properties to 7,8-dihydroxyflavone. Ye says his laboratory has already identified compounds that are several times more active. The next step is more animal studies to choose compounds likely to have the best drug profiles: stable and non-toxic.
Manuel Yepes, MD, assistant professor of neurology at Emory University School of Medicine, and his colleagues performed the stroke model experiments. Gary Miller, PhD, associate professor in Emory’s Rollins School of Public Health, and his colleagues performed the Parkinson’s-simulating toxin experiments.
Investigators from Georgia State University, UCLA, and the Centers for Disease Control and Prevention contributed to the research, which was supported by the National Institutes of Health.
Ye is an inventor of novel technology related to this research. Under Emory policies, he is eligible to receive a portion of any royalties or fees received by Emory from this technology. These relationships have been reviewed and approved by Emory University in compliance with its conflict of interest policies.
S.W. Jang, X. Liu, M. Yepes, K.R. Shepherd, G.W. Miller, Y. Liu, W.D. Wilson, G. Xiao, B. Blanchi, Y.E. Sun, and K. Ye.
A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. PNAS ##,## (2010)
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Compounds that help protect nerve cells discovered by Duke team
Last Updated on Thursday, 6 May 2010 02:45 Written by Editor Thursday, 6 May 2010 02:45
DURHAM, N.C. – Scientists at Duke University Medical Center have found some compounds that improve a cell’s ability to properly “fold” proteins and could lead to promising drugs for degenerative nerve diseases, including Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.
Misfolded proteins in nerve cells (neurons) are a common factor in all of these diseases. The Duke team has identified many new chemicals that activate a master regulator to increase the supply of “protein chaperone” molecules that help fold proteins properly.
The scientists further explored one of the candidate molecules to activate the master regulator of chaperone gene expression, Heat Shock Factor 1 (HSF1), to learn whether it would work in model systems of Huntington’s disease, a devastating neurodegenerative disease of protein misfolding.
They were able to show that the molecule stimulated protein chaperones in cells and in an animal system. The damage to early-state rat neurons was much lower in cells pre-treated with the HSF1 activator, and damage to the neurons of fruit flies that had a Huntington’s-like disorder was also greatly reduced.
Previous studies suggested that elevating the abundance of protein chaperones is effective in treating cell and animal models of Huntington’s and Parkinson’s diseases. This work provides a new approach to address the root cause of these diseases — protein misfolding. Earlier attempts had used heat shock and other approaches that stress a nerve cell in order to produce more chaperone molecules, but at a cost of damaging the cell to save it.
“The advantage of our screen is that it identifies molecules that can elevate the levels of chaperones without inducing cellular stress and that don’t inhibit a key protein chaperone called Hsp90 that is needed for cells to function normally,” said senior author Dennis J. Thiele, Ph.D., Professor of Pharmacology and Cancer Biology. “We found a creative way to identify new molecules that can activate the body’s natural protein folding machinery.”
The research was published in the Jan. 19 online issue of PLoS Biology.
Lead author Daniel Neef, Ph.D., says they used genetically altered yeast to find compounds that might aid chaperone development. The scientists took yeast with a deleted HSF1 (master regulator) gene and inserted the related human HSF1 gene. These yeast, however, still weren’t able to activate human HSF1 on their own, and in effect, died. They needed an additional molecule to make human HSF1 become active.
The team put these “humanized yeasts” into wells and started testing compounds that would provide the missing link. In several of the wells, if the compound worked, the yeast started multiplying. “Out of over 12,000 compounds tested from chemical libraries, about 50 compounds worked,” Neef said. The team decided to explore one of these compounds (HSF1A) in further experiments.
“The humanized yeast-based screening results in our study provide a way to identify new classes of small molecules, small enough to penetrate the blood-brain barrier to work in neurons, in flies as well as in humans,” Thiele said. “These small molecules may be effective therapies in neurodegenerative diseases caused by protein conformational disorders such as Huntington’s, Alzheimer’s and Parkinson’s disease.”
The scientists found that HSF1A could stimulate more protein chaperones and reduce the protein misfolding. They showed that adding a small amount of HSF1A to the developing rat neurons kept the proteins dissolved throughout the cell, rather than clumping visibly as speckled areas (as seen under microscopes).
“We enhanced the cells’ viability by four or five times by pre-treating them with this molecule,” Neef said. “Otherwise, the cells would have died.”
They used fruit flies with Huntington’s disease for experiments to prove that the principle would work in an animal. Adding HSF1A to the fly’s food produced more chaperone molecules in their neurons. This suggests that the molecule could travel from the fly’s stomach into its circulation and cross a barrier to the fly brain.
In the key experiment, the Huntington’s disease flies received either their usual food or food plus HSF1A. Those with untreated food developed eyes with dying photoreceptor neurons and lacking the normal red color. Those that ate HSF1A went on to have normal-colored eyes, indicating a repair had taken place, just by eating food laced with the promising compound.
source: eurekalert.org
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Proteins That Might Contribute to Memory Loss and Alzheimer’s Disease Identified
Last Updated on Thursday, 6 May 2010 11:53 Written by Editor Thursday, 6 May 2010 11:53
ScienceDaily (Jan. 17, 2010) — A scientific group led by the Translational Genomics Research Institute (TGen) have identified three kinases, or proteins, that dismantle connections within brain cells, which may lead to memory loss associated with Alzheimer’s disease.
These findings, the results of a multi-year TGen study, are published in this month’s edition of BMC Genomics in a paper titled: High-content siRNA screening of the kinome identifies kinases involved in Alzheimer’s disease-related tau hyperphosphorylation.The three kinases were found to cause a malfunction in tau, a protein critical to the formation of the microtubule bridges within brain cells, or neurons. These bridges support the synaptic connections that, like computer circuits, allow neurons to communicate with each other.
“The ultimate result of tau dysfunction is that neurons lose their connections to other neurons, and when neurons are no longer communicating, that has profound effects on cognition — the ability to think and reason,” said Dr. Travis Dunckley, an Associate Investigator in TGen’s Neurodegenerative Research Unit and the scientific paper’s senior author.
Tau performs a critical role in the brain by helping bind together microtubules, which are sub-cellular structures that create scaffolding in the neurons, allowing them to stretch out along bridges called axons. The axons support the synaptic, or chemical, connections with other neurons.
Under normal circumstances, kinases regulate tau by adding phosphates. This process, called tau phosphorylation, enables the microtubules to unbind and then bind again, allowing brain cells to connect and reconnect with other brain cells.
“That facilitates synaptic plasticity. It facilitates the ability of people to form new memories — to form new connections between different neurons — and maintain those memories. So, it’s an essential function,” Dr. Dunckley said.
However, sometimes the tau protein becomes hyperphosphorylated, a condition in which the tau creates neurofibrillary tangles, one of the signature indicators of Alzheimer’s.
“When tau protein is hyperphosphorylated, the microtubule comes apart — basically destroying that bridge — and the neurons can no longer communicate with each other,” Dr. Dunckley said.
TGen investigators created sophisticated tests to look at all 572 known and theoretical kinases within human cells. They identified 26 associated with the phosphorylation of tau. Of these 26, three of them — EIF2AK2, DYRK1A and AKAP13 — were found to cause hyperphosphorylation of tau, permanently dismantling the microtubule bridges.
“This paper shows, for the first time, these three kinases affect Alzheimer’s disease-relevant tau hyperphosphorylation, in which most of the tau protein is now driven into a permanently phosphorylated form,” Dr. Dunckley said.
Dr. Eric Reiman, clinical director of TGen’s Neurogenomics Division and executive director of the Banner Alzheimer’s Institute, explained that tau holds together the skeleton inside neurons. When phosphate molecules stick to tau proteins, the skeleton falls apart and the neurons begin to retract their synaptic branches and die, leading to memory loss and thinking problems.
In this study, researchers used a molecular tool called siRNA to screen the entire human genome, said Dr. Reiman, a co-author of the scientific paper. This tool enabled the TGen-led team to discover which proteins, when genetically turned off, prevent phosphate molecules from sticking to tau. The three kinases, or proteins, that appear to contribute to the formation of brain tangles, can now be targeted by protein-inhibitor drugs.
“This study used a powerful tool to discover three proteins that may be involved in tangle formation. If safe and well-tolerated tangle-busting medications can be developed, they offer great promise in the treatment of Alzheimer’s disease,” said Dr. Reiman, who also is Director of the Arizona Alzheimer’s Consortium.
The next step will be to identify drug compounds that can negate the effects of the three kinases linked to tau hyperphosphorylation.
“The reason that we did this study was to identify therapeutic targets for Alzheimer’s disease, whereby we could modify the progression of tau pathology,” Dr. Dunckley said. “This was a screen to identify what the relevant targets are. Now, we want to match those targets to treatments.”
TGen’s collaborators in the study included: the Department of Neurology at the Mayo Clinic in Jacksonville, Fla.; the Center for Alzheimer’s Research at the Sun Health Institute in Sun City, Ariz.; Banner Alzheimer’s Institute in Phoenix, Ariz.; the Department of Psychiatry at the University of Arizona; and the Arizona Alzheimer’s Consortium, a group of nine institutes that cooperatively study Alzheimer’s disease.
source: sciencedaily.com
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Forget to take your Ginkgo biloba? Turns out, it doesn’t matter
Last Updated on Wednesday, 5 May 2010 02:37 Written by Editor Wednesday, 5 May 2010 02:37
Among the natural products on pharmacy shelves, I was rooting for Ginkgo biloba for the prevention of dementia. For one, dementia is a horrible illness. Secondly, currently available drugs for Alzheimer’s disease (AD) have little meaningful effect. Thirdly, preliminary data with ginkgo for AD looked encouraging. I recall reading this systematic review back in 2000. One sentence jumped out at me (the bolding is mine):
We conclude that for selegiline, vitamin E, lecithin, linopirdine, and propentofylline the published data do not provide support for efficacy. Based on the evidence we reviewed, it is our conclusion that donepezil, metrifonate and rivastigmine, however, all provide statistically significant modest benefit on cognitive performance and global functioning to the elderly with probable AD who are eligible for inclusion in clinical trials. The magnitude of the effect is similar for all of the medications. The results from the trials of ginkgo biloba are promising but the effects are smaller than those from the above mentioned therapies.
So the effect, while weak, was just about as bad as the prescription alternatives. For a “natural†remedy, that’s pretty good. But as with most small clinical trials, what appears to be clinically and statistically significant usually disappears when larger, more rigorous trials are conducted. And that seems to be the case now, with a publication in the December 23, 2009 issue of the Journal of the American Medical Association. But before we dive into the trial, let’s look at why ginkgo is even being studied at all.
The Background
 Ginkgo biloba is a popular product – it’s the most prescribed supplement in Germany (and apparently the treatment of choice for dementia), and is #9 in sales among herbals in the United States ($99 million in 2008).Ginkgo trees are not only attractive, but their leaves are used to make the medicinal product, usually in the form of an extract. (Ginkgo seeds contain a toxin and are considered unsafe for consumption.) Ginkgo leaves contain several biologically active compounds including flavonoid glycosides and terpinoids. With respect to prevention or treatment of dementia, it’s been proposed that the constituents might work by reducing oxidative damage to neurons, or from providing general anti-inflammatory effect. It has also been proposed that ginkgo improves circulation, perhaps through an antiplatelet effect. Another possible mechanism is that ginkgo might have direct effects by reducing cell death – though this has not been established.
Ginkgo biloba supplements are usually well tolerated. Side effects are typically mild, with stomach upset the most common complaint. Spontaneous bleeding is the most concerning rare side effect reported with treatment, and there are several case reports of bleeding in the brain and eye that are associated with ginkgo treatment. It’s not certain that ginkgo is the cause, but it’s troubling. Clinical trial results have been reassuring on this point, with reported side effects largely equivalent to placebo. Still, the known antiplatelet effects, and the bleeding case reports, have led to warnings about use in combination with other antiplatelet drugs. It’s not recommended for people with a history of bleeding problems, or in combination with medications that can increase bleeding risks (warfarin, anti-inflammatories, etc.) Ginkgo seems to reduce the action of some liver enzymes, so it can indirectly affect other drugs as well. Combining ginkgo with any medications, in the absence of consultation with a pharmacist, is not advised.
Ginkgo has been studied extensively, albeit in small, short-duration trials. The Natural Medicines Comprehensive Database rates it “Possibly Effective†for age-related memory impairment, cognitive function, dementia, diabetic retinopathy, peripheral artery disease, premenstural syndrome, Raynaud’s syndrome, and vertigo.
Digging into the dementia research, the issue of poor trial quality is repeatedly cited as a confounder in interpreting the data. Indirect comparisons, like the systematic review cited above, have suggested that if ginkgo does has an effect, it’s more modest than drug treatment.
Before we look at the latest trial, let’s consider how what we’re studying and how we look for an effect. Alzheimer’s is the most common form of dementia in adults. It is progressive, and non-reversible. From the National Institute of Neurological Disorders and Stroke,
Initially, people experience memory loss and confusion, which may be mistaken for the kinds of memory changes that are sometimes associated with normal aging. However, the symptoms of AD gradually lead to behavior and personality changes, a decline in cognitive abilities such as decision-making and language skills, and problems recognizing family and friends. AD ultimately leads to a severe loss of mental function. These losses are related to the worsening breakdown of the connections between certain neurons in the brain and their eventual death.
Evaluating whether a drug (or “natural†remedy) works to prevent dementia is challenging. The disease course is a progressive decline in function – the intent with treatment is to prevent, slow, or delay, that decline. Randomized, controlled, double-blind trials are essential – it is impossible to determine if any treatment has an effect without comparisons to a control group. Because of the challenges with diagnosis, the slow onset, and the gradual decline in function, clinical trials need to be designed carefully. A good trial would follow a large number of patients for a long period. It would also study a large population, so that even a modest effect could be detected. We’d also want to study a population that’s healthy – without dementia, but we might include those with mild cognitive impairment. This would help us answer whether ginkgo useful to prevent dementia.
And that’s exactly what this study set out to answer.
The Study
The Snitz et al study was a follow-on study to the DeKosy et al study published in JAMA in 2008. Briefly, DeKosy established that Ginkgo biloba was not effective in reducing the incidence of dementia or Alzheimer’s disease. This newest study reports on cognitive decline, a pre-defined secondary outcome in the same population as the DeKosy study. The authors sought to determine if Ginkgo biloba affected the rated of cognitive change, and if it had specific effects on different cognitive functions (e.g., memory, language, attention, etc.)
Volunteers aged 75 or older were recruited in four US cities. Those with dementia were excluded, though mild cognitive impairment was acceptable. If you weren’t taking drugs that could interact with ginkgo, and were generally healthy, you were probably eligible for the study. It was a good generalizable sample of the elderly population. This was a huge study: 3069 patients were randomized. The population size was selected to accommodate for patients that would drop out, yet still be large enough to detect a clinically meaningful difference from the ginkgo.
Patients were randomized to either Ginkgo biloba 120mg twice daily (“EGb 761“, donated by Schwabe Pharmaceuticals) or an identical placebo. This brand of ginkgo biloba is standardized to the main active ingredients, and the dose was chosen based on results from prior clinical trials. Both patients and researchers were blinded to the actual treatment given.
Patients were evaluated when they entered the trial, and regularly with two validated dementia screening test, the 3MSE and the ADAS-Cog. Comprehensive neurological testing was conducted annually starting in the third year of the study. Patients were followed, on average, for 6.1 years in total.
The results can be summarized simply: There was no significant difference between the groups, either overall or in any of the specific cognitive areas tested. There is no evidence that ginkgo has any effect on those that develop dementia, or on cognitive effects of normal aging.
To see if “pre-treating†patients with ginkgo had any effect, the researchers compared results from years 3 to 4 to year 6. Again, no effect.
Criticisms of the Study
The manufacturer of the ginkgo supplement used, Schwabe, dismisses the results. Their criticisms can be summarized as follows, with my comments in [brackets]:
- The placebo group barely declined in function. Ginkgo cannot be shown to be effective when the control group declines so little. [Because of a lower than expected dementia rate in the trial, the trial was extended until the required number of dementia cases occurred that would be sufficient to detect a difference. No difference was noted between the groups.]
- Cognitive performance was measured using a blunt dementia-screening tool. Specific testing didn’t start until 500 patients had left the study. [The authors note this, and did a secondary analysis which was consistent with the primary analysis. The "blunt" screening tools are validated evaluation tools for dementia (3MSE and ADAS-Cog. No difference was noted between groups.]
- Of patients that remained in the study, only 60% (placebo and ginkgo) were taking the product. [The study was powered to adjust for this, as non-adherence was evaluated in the intention-to-treat analysis. Notably, adherence was slightly lower (though not significantly) in the ginkgo group.]
Conclusion
The largest and best-designed study to examine Ginkgo biloba has found it ineffective in reducing the incidence of dementia, Alzheimer’s disease, or in reducing the rate of cognitive decline in older adults. This is a persuasive study. In a population that is very close to the “real world†that might consider taking the product, no effect of ginkgo has been shown. The product studied was the most-evaluated ginkgo product and one standardized for active ingredients. Given the documented risks of bleeding with ginkgo, the risk-benefit calculation now tilts strongly away from treatment: There are risks, and no demonstrated benefits. It’s time for pharmacists to start recommending against self-treatment with Ginkgo biloba for the treatment or prevention of dementia or cognitive decline.
References
Snitz, B., O’Meara, E., Carlson, M., Arnold, A., Ives, D., Rapp, S., Saxton, J., Lopez, O., Dunn, L., Sink, K., DeKosky, S., & , . (2009). Ginkgo biloba for Preventing Cognitive Decline in Older Adults: A Randomized Trial JAMA: The Journal of the American Medical Association, 302 (24), 2663-2670 DOI: 10.1001/jama.2009.1913.
Up-To-Date. Ginkgo Biloba. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2009.
Natural Medicines Comprehensive Database [database on the Internet]. Stockton (CA): Therapeutic Research Faculty; 1995-2010 [cited 2 Jan 2010] Available from: http://www.naturaldatabase.com. Subscription required to view.
source: sciencebasedpharmacy.wordpress.com
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Alzheimer’s Study Leads To Better Drug For Infections
Last Updated on Friday, 29 January 2010 10:55 Written by Editor Friday, 29 January 2010 10:55
Research into Alzheimer’s disease seems an unlikely approach to yield a better way to fight urinary tract infections (UTIs), but that’s what scientists at Washington University School of Medicine in St. Louis and elsewhere recently reported.
One element links the disparate areas of research: amyloids, which are fibrous, sticky protein aggregates. Some infectious bacteria use amyloids to attach to host cells and to build biofilms, which are bacterial communities bound together in a film that helps resist antibiotics and immune attacks. Amyloids also form in the nervous system in Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders.
To probe amyloids’ contributions to neurodegenerative diseases, scientists altered potential UTI-fighting compounds originally selected for their ability to block bacteria’s ability to make amyloids and form biofilms. But when they brought the compounds back to UTI research after the neurology studies, they found the changes had also unexpectedly made them more effective UTI treatments.
“Thanks to this research, we have evidence for the first time that we may be able to use a single compound to impair both the bacteria’s ability to start infections and their ability to defend themselves in biofilms,” says senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University.
The findings were reported online in Nature Chemical Biology.
The National Institutes of Health has estimated that over 80 percent of microbial infections are caused by bacteria growing in a biofilm, according to Hultgren. Scientists in Hultgren’s laboratory have worked for decades to understand the links between biofilms and UTIs.
“UTIs occur mainly in women and cause around $1.6 billion in medical expenses every year in the United States,” says co-lead author Jerome S. Pinkner, laboratory manager for Hultgren. “We think it’s likely that women who are troubled by recurrent bouts of UTIs are actually being plagued by a single persistent infection that hides in biofilms to elude treatment.”
Co-lead author Matthew R. Chapman, Ph.D., now associate professor of molecular, cellular and developmental biology at the University of Michigan, was a postdoctoral fellow in Hultgren’s lab in 2002 when he discovered that the same bacterium that causes most UTIs, Escherichia coli, deliberately makes amyloids. The amyloids go into fibers known as curli that are extruded by the bacteria to strengthen the structures of biofilms.
To treat UTIs, Hultgren’s lab has been working with Fredrik Almqvist, Ph.D., a chemist at the University of Umea in Sweden, to develop compounds that block bacteria’s ability to make curli, disrupting their ability to make biofilms and leaving them more vulnerable to antibiotics or immune system attacks. Almqvist recently suggested altering a group of the most promising curli-blockers to see if they could also block the processes that form amyloids in Alzheimer’s disease.
The alterations worked: In laboratory tests, the new compounds prevented the protein fragment known as amyloid beta from aggregating into amyloid plaques like those found in the brain in Alzheimer’s disease. When scientists took the new compounds back to a mouse model of UTIs, though, they received a surprise. The altered compounds were better at reducing the virulence of infections, inhibiting not only curli formation but also the formation of a second type of bacterial fibers, the pili.
“Pili aren’t made of amyloids, but they are essential to both biofilms and to the bacteria’s ability to initiate an infection,” Hultgren says.
Hultgren and colleagues are already developing even more potent infection and amyloid fighters, screening a library of thousands of chemicals similar to the most promising compounds from the study.
Chapman cautions that it’s too early to tell which, if any, of the compounds will be helpful in treating neurodegenerative diseases.
“Much neurodegenerative drug development has focused on ways to break up amyloids or prevent them from forming, but because amyloids may also be an important part of normal cellular physiology, we need to identify molecules that will target only the toxic amyloid state,” he says.
Cegelski L, Pinkner JS, Hammer ND, Cusumano CK, Hung CS, Chorell E, Aberg V, Walker JN, Seed PC, Almqvist F, Chapman MR, Hultgren SJ. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nature Chemical Biology, published online.
Funding from the Swedish Natural Science Research Council, the Knut and Alice Wallenberg Foundation, the National Institutes of Health and the Burroughs Wellcome Fund supported this research.
Source
Washington University in St. Louis
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New drug turns Alzheimer’s theory on its head
Last Updated on Friday, 21 August 2009 02:30 Written by Editor Friday, 21 August 2009 02:30
Researchers investigating the causes of Alzheimer’s disease have been left puzzled by data showing that the antihistamine dimebolin, a drug with promising activity in improving Alzheimer’s symptoms, actually seems to increase levels of the toxic protein beta amyloid.
For years it has been thought that the degeneration of nerves seen in Alzheimer’s disease was a result of exposure to the protein fragment beta amyloid. In healthy brains the fragments are broken down and eliminated, while in Alzheimer’s they accumulate to form insoluble plaques.
Results from a Phase II clinical trial reported last year found that dimebolin was around two-and-a-half times more effective than current medicines such as Pfizer and Eisai’s Aricept (donepezil) in improving cognition and memory in Alzheimer’s patients.
The drug’s activity in Alzheimer’s was discovered serendipitously when Russian scientist Sergey Bachurin was screening a number of compounds that could block both cholinesterase and NMDA (N-methyl-D-aspartic acid) – the targets for the current generation of Alzheimer’s treatments. It is currently being tested in Phase III clinical trials by US biopharmaceutical firm Medivation in collaboration with Pfizer.
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The antihistamine dimebolin has raised doubts about what we know about Alzheimer’s
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However, results from the latest experiments in mice, reported at a meeting in Vienna last week, indicate that dimebolin actually appears to increase levels of beta amyloid – undermining the idea that the plaques themselves are toxic. The results also raise questions about many of the other drugs that are being developed to treat the disease.
Samuel Gandy of the Mount Sinai School of Medicine in New York, who carried out the experiments, told Chemistry World that the findings were surprising. ‘Conventional wisdom in the field, regardless of one’s position on ‘the amyloid hypothesis’, is that an amyloid benefit would mean amyloid-lowering.’
‘The latest findings don’t mean we should toss amyloid,’ he says. ‘But we should be prepared to consider unconventional possibilities.’
Clive Ballard, research director of the Alzheimer’s Society in the UK, concurs with that view. ‘The data tie in with an alternative hypothesis, namely that other forms of amyloid – such as soluble amyloid oligomers – may actually be more neurotoxic than insoluble plaques, he says.
One school of thought is that plaques may in fact represent a protective mechanism in which the body sequesters toxic forms of amyloid to render them harmless. ‘The Gandy research may be showing that dimebolin is driving this process, stimulating conversion of amyloid strands into a non-toxic form,’ suggests Ballard.
The problem for the pharmaceutical sector is that some of the new drugs coming through late-stage clinical testing, including Wyeth and Elan Pharmaceuticals’ much-anticipated antibody bapineuzumab are designed to break down the plaques.
Gandy believes researchers should also be looking at what is going on with amyloid inside nerve cells, rather than the external manifestations of amyloid processing.
‘We should perhaps be paying more attention to intracellular oligomers,’ he says. ’There are mice models with elevated intraneuronal oligomers and these show impaired functions, so this is certainly an avenue worth exploring.’
Other drugs in the pharmaceutical pipeline, such as the gamma secretase inhibitor class being developed by Eli Lilly, Bristol-Myers Squibb and others might lower intracellular beta amyloid levels.
‘However, we might need different drugs from the ones that we have, all of which are optimised to lower beta amyloid levels in the cerebrospinal fluid and interstitial fluid,’ says Gandy.
Source: rsc.org
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Early testing for Alzheimer’s – Spinal fluid compounds can predict in many cases whether people with mild cognitive impairments will develop the disease
Last Updated on Friday, 21 August 2009 02:22 Written by Editor Friday, 21 August 2009 02:22
Elderly people with mild cognitive losses are at a heightened risk of progressing to Alzheimer’s disease if they have a combination of telltale compounds in their spinal fluid, researchers report in the July 22/29 Journal of the American Medical Association.
By testing for a shortage of a sticky compound called amyloid-beta in the spinal fluid and for excess amounts of two kinds of a protein called tau, the scientists could identify people at greatest risk.
The test isn’t foolproof, and a positive reading still warns of a disease for which there is no cure. But scientists are heartened by this and earlier studies (SN: 9/20/03, p. 179)because Alzheimer’s disease is difficult to foresee and its early symptoms are often mistaken for routine cognitive losses caused by aging.
Niklas Mattsson of a Gothenburg University-affiliated hospital in Mölndal, Sweden, and an international group of scientists recruited 750 elderly people in Europe and the United States from 1990 to 2007. At the time of enrollment, the volunteers had mild cognitive impairment — a loss of memory or other mental faculties — that wasn’t attributable to aging alone but fell short of Alzheimer’s disease. Each volunteer contributed a cerebrospinal fluid sample by undergoing a spinal puncture. The participants, average age 69, were monitored for about three years during the study.
Those who developed Alzheimer’s disease were more likely to have had less amyloid-beta or more tau in their spinal fluid than those who didn’t develop Alzheimer’s. People who had both low amyloid-beta and high tau levels were five times as likely to develop Alzheimer’s disease during the study as were those with normal spinal fluid profiles, Mattsson says.
The screening test correctly predicted incipient Alzheimer’s disease 83 percent of the time. Studies that track elderly patients longer may show an increased accuracy rate because patients whose spinal fluid tested positive may develop Alzheimer’s disease later, says Ronald Petersen, a neurologist at the Mayo Clinic in Rochester, Minn.
Since spinal fluid bathes the entire central nervous system, its components can serve as markers for what’s going on in the brain. Although the precise biological course of Alzheimer’s is murky, many scientists theorize that amyloid-beta accumulates in the brain early in the disease process, leaving less to circulate in the spinal fluid, Petersen says. Later, tau is released from dying brain cells into the spinal fluid, increasing tau levels there.
Roughly half of all elderly people with mild cognitive impairments later develop Alzheimer’s disease, says Mattsson, a physician and neuroscientist. Currently available drugs treat only Alzheimer’s symptoms, not the disease.
By fine-tuning this screening test, Mattsson, Petersen and others are planning for the day when other research teams develop drugs to arrest or reverse the brain damage that marks the disease. There are up to 100 such experimental Alzheimer’s drugs currently in development, Petersen says. “Almost every major pharmaceutical house has a program for Alzheimer’s.â€
If such medications become available, accurate diagnosis will become paramount in determining how to prescribe them, Mattsson says. “It’s very important to interfere with the disease as early as possible, and this is where the diagnostic test comes in.†Screening for changes in amyloid-beta and tau in drug trial participants might also indicate which medications are thwarting the disease process, Mattsson says.
Source: Sciencenews.org
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Cognition Therapeutics Closes Series A Financing to Advance Drug Candidates for Alzheimer’s Disease
Last Updated on Friday, 21 August 2009 01:12 Written by Editor Friday, 21 August 2009 01:12
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Start-up company continues momentum with selection of disease-modifying small molecule drug leads for behavioral testing
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PITTSBURGH, July 16 /PRNewswire/ — Cognition Therapeutics Inc., a Pittsburgh-based drug discovery company developing small molecule disease-modifying treatments for Alzheimer’s, has closed on a $1.21M Series A financing. The round was led by Ogden CAP, LLC of New York City and includes M5Invest Partners of Villanova, PA, the Pittsburgh Life Sciences Greenhouse, Innovation Works (Pittsburgh), and several individual investors. The round included both new investments and the conversion of existing convertible notes.
“This investment facilitates the advancement of our existing lead molecules towards a major milestone,” said Cognition Therapeutics President and CEO Hank Safferstein, Ph.D., J.D. “Our combination of novel, small molecule drug candidates and biologically-relevant screening methods is unique in the pharmaceutical industry. We’re pleased to have Ogden CAP and M5Invest join our other investors in supporting our pioneering approach to treat or prevent Alzheimer’s disease by targeting the proteins that cause the earliest stages of this disease”. “As early investors, we are impressed by Cognition Therapeutics’ combination of cutting-edge technology, influential and experienced leadership, and large clinical and commercial potential,” said Robert Gailus, senior advisor to Ogden CAP. “Alzheimer’s disease is a major health epidemic that places increasing strains on the world’s healthcare systems as the population ages. The drug candidates being developed by Cognition have the potential to significantly impact this devastating disease,” Gailus continued. Alzheimer’s disease affects an estimated four and a half million people in the United States today. That number is expected to exceed 12 million people by 2050. Funds raised in this round will support advancement of Cognition Therapeutics’ pioneering lead molecules that block the activity of the toxic oligomeric form of Abeta protein that interferes with normal learning and memory. Studies from the world’s leading academic laboratories indicate that the memory deficits caused by the oligomeric protein are among the earliest changes seen in Alzheimer’s disease and Mild Cognitive Impairment, the precursor to Alzheimer’s. These studies indicate that blocking the effects of this protein may halt or reverse Alzheimer’s disease. Cognition will use these funds to test its most promising lead molecules in behavioral models of Alzheimer’s disease. “The advancement of the company’s lead compounds into behavioral testing represents a significant milestone for the company,” says Dr. Franz Hefti, Chairman of the Board. “Cognition’s scientific approach is unique among the approaches being taken by the pharmaceutical industry today. Cognition has a novel Alzheimer’s disease model for the critical molecular step that causes memory loss. In addition, the company’s proprietary chemistry is based on natural molecular scaffolds which brought us effective drugs like aspirin, lidocaine and taxol. We anticipate new disease-modifying drugs for Alzheimer’s disease will result from this unique combination,” Dr. Hefti continued. About Cognition Cognition Therapeutics, Inc. is a leader in the discovery and development of small molecule therapeutics targeting the toxic proteins that cause the cognitive decline associated with Alzheimer’s disease and other degenerative diseases of the human brain. Toxic proteins play a crucial role in a large class of diseases, and there are currently no therapeutics available to prevent or block the destructive effects of toxic oligomeric proteins. Cognition has leveraged its scientific expertise with these difficult targets to pioneer the use of proprietary assays that emphasize functional responses and proprietary medicinal chemistry that ensures novel, high quality small-molecule drug candidates for the treatment of these diseases. Cognition has developed a number of screening strategies to identify small molecules capable of blocking the central toxicity of proteins in Alzheimer’s disease and other neurodegenerative diseases. These assays emphasize phenotypic or functional responses of mature primary neurons to the toxic proteins. Cognition’s proprietary chemistry platform converts natural products into low molecular weight chemically stable druglike molecules, and is thus a source of novel pharmacophores and valuable drug candidates. These two technology platforms harken back to the origins of the pharmaceutical industry, when phenotypic responses were the sole screening method and natural product derivatives formed the starting materials for successful drug discovery. Cognition Therapeutics was founded on small molecule chemical libraries licensed from co-founder Dr. Gilbert Rishton at California State University Channel Islands and proprietary screening strategies established by co-founder and Chief Science Officer Dr. Susan Catalano. After initial investment and relocation to Pittsburgh, the company secured Dr. Hank Safferstein as President and CEO, bringing with him more than 15 years of leadership experience in drug development, commercialization and marketing for a number of public and private companies. www.cogrx.com. About Ogden CAP, LLC Ogden CAP, LLC is a New York company that has investments is a wide variety of asset classes, including venture capital. Over the past two years Ogden CAP, LLC has invested in 10 early stage companies. Besides its investment in Cognition, Ogden CAP, LLC has two other investments in the Pittsburgh area: FASTTAC, a document control and management company for the construction industry, and TSG, Inc. an energy company that converts coal to fuels. About the Pittsburgh Life Sciences Greenhouse (PLSG) The Pittsburgh Life Sciences Greenhouse (PLSG) provides capital investments and customized company formation and business growth services to western Pennsylvania’s life sciences enterprises. The PLSG supports biosciences companies with promising innovations in the following concentrations: Biotechnology Tools, Diagnostics, Healthcare IT, Medical Devices and Therapeutics. The PLSG is propelling the sustainable growth of the region’s life sciences economy by accelerating research and technology commercialization with seed and early-stage companies; connecting investors with their Investment Portfolio companies; expanding established life sciences ventures and relocating biomedical companies to Pennsylvania. About Innovation Works (IW) Innovation Works provides risk capital and business expertise to the most promising early-stage technology companies in Southwestern PA to help them grow and succeed. Innovation Works is one of the most active seed-stage investors in the country, having invested in more than 120 emerging technology companies since beginning their seed fund in 1999. Those companies have gone on to raise over $600 million in additional capital from a diverse set of VCs, private investors, strategic partners and other sources of capital. |
SOURCE Cognition Therapeutics Inc.
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Green protein inhibits Alheimer’s, CSIRO scientists find
Last Updated on Thursday, 20 November 2008 03:42 Written by Editor Thursday, 20 November 2008 03:42
BY NYSSA SKILTON
MEDICAL REPORTER
18/11/2008
CSIRO scientists have developed a way to screen for compounds that can inhibit the progression of Alzheimer’s disease.
The system involves using live yeast and a protein called Abeta fused to a fluorescent green protein, which comes from jellyfish.
The scientists, working within CSIRO’s Preventive Health Flagship, published their findings in the latest edition of the Journal of Alzheimer’s Disease.
Alzheimer’s disease is the fourth leading cause of death in people older than 65 and there is no cure known to science.
It is thought to be the result of a loss of neurons in the brain, caused by a process in which toxic forms, known as multimers, of the small Abeta protein are created.
Lead author Ian Macreadie said the scientists had discovered a ”rapid screening system” to identify inhibitors of this process.
”Compounds that inhibit the formation of the toxic multimers may lead to the prevention or delay of the disease,” Dr Macreadie said.
”The yeast trial we developed could lead to the discovery of new agents which may prove useful in preventing or delaying the onset of Alzheimer’s disease.”
The researchers tested their screening system using folate, a nutrient known to protect against Alzheimer’s disease. They found that the folate made the yeast with the jellyfish protein greener.
The green colour signifies that the additive, in this case the folate, has stopped the Abeta protein from changing into its toxic forms.
”The greener the better,” Dr Macreadie said. ”We’re interested in finding not just folate, but many existing compounds and novel compounds that may be helpful in [combating] Alzheimer’s.”
The researchers have already screened hundreds of compounds in the search for Alzheimer’s inhibitors. They plan to screen foods to identify nutrients they may use to enrich foods to protect consumers.
Posted under Alzheimer's disease, Australia, Compound Libraries, Discoveries, Innovations and Patents, Industry News, News by Region, News by Subject, Press Releases, R & D | Comments Off
Scientists seek out Alzheimer’s enemies
Last Updated on Thursday, 20 November 2008 03:24 Written by Editor Thursday, 20 November 2008 03:24
CSIRO scientists have developed a new system to screen for compounds that can inhibit one of the processes that takes place during the progression of Alzheimer’s disease.
In a paper published in the Journal of Alzheimer’s Disease, folate is shown to be beneficial in the screening system.
Lead author, CSIRO’s Dr Ian Macreadie says folate is already well known to have a protective effect against Alzheimer’s disease which is believed to be caused by the loss of neurons in the brain due to a process whereby toxic multimers of a small protein called Aβ are formed.
“However, a team of scientists working within CSIRO’s Preventative Health Flagship has discovered a rapid screening system to identify inhibitors of this process. Compounds that inhibit the formation of the toxic multimers may lead to the prevention or delay of the disease,†Dr Macreadie says.
“Although many other research groups and drug companies around the world are trying to find compounds that act in the same way, the advance by the Flagship team involves using live yeast with the Aβ protein fused to a green fluorescent protein that comes from jellyfish.
“The significance of this development is that the yeast trial we developed could lead to the discovery of new agents which may prove useful in preventing or delaying the onset of Alzheimer’s disease.â€
Currently Alzheimer’s disease is an incurable illness and the fourth leading cause of death in people aged 65 years and over.
Although folate is abundant in foods like leafy green vegetables, pulses and liver, CSIRO studies have shown that many Australians do not consume enough folate to benefit from its ability to prevent cell damage. Folate levels can, however, be readily restored by dietary folate supplementation.
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