A new drug discovery tool for Alzheimer's

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An article published in the April issue of the Journal of Alzheimer's Disease presents a detailed characterization of a new drug discovery tool for Alzheimer's disease. It demonstrates that an abnormal form of tau protein, as it occurs in Alzheimer's disease, can be produced in very simple cell models in an unambiguous way. Most importantly, it also shows an example of a chemical compound, found in nature, which is highly effective to completely suppress the abnormal changes of tau.

A simple cellular assay for the pathological modification of tau protein by abnormal hyperphosphorylation, as seen in Alzheimer's disease and a variety of other neurological disorders (tauopathies), has been developed by researchers at Sirenade Pharmaceuticals AG in Munich, Germany. The assay can be used to screen for drugs against these disorders, and the discovery of a very effective small molecule is described as an example.

Tau proteins are a family of neuron-specific proteins believed to play an important role in the organization of the skeleton of nerve cells. This protein has been known to be abnormally modified in degenerating neurons in Alzheimer's disease in a process called neurofibrillary degeneration. This form of neurodegeneration is thought to be a dominant cause of the massive loss of brain mass and function in many dementias, and its inhibition can be expected to change the prognosis of Alzheimer's disease significantly.

Cell models are essential tools to analyze the molecular mechanisms involved in specific disease processes, and also the mechanisms of drugs, which act against them. For the process of tau hyperphosphorylation, credible models with utility for drug discovery have not been established to date. The model developed at Sirenade AG under the leadership of Dr. Hanno Roder, now at TauTaTis, Inc., fills this important gap. http://www.medicalnewstoday.com .

Curcumin may offer diabetes benefits: study
Curcumin, the natural pigment that gives the spice turmeric its yellow colour, could have benefits for diabetics, suggests a joint Korean-American study. http://www.nutraingredients.com

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Alzheimer's and low oxygen

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In studies of human brain cells, the widely-used anesthetic desflurane does not contribute to increased production of amyloid-beta protein; however, when combined with low oxygen conditions, it can produce more of this Alzheimer's associated protein.

Over 200 million people undergo surgery each year, and there has been concern that anesthetic use may contribute to Alzheimer's and other brain disorders. It were subjected human brain cells to 12% desflurane for six hours (mimicking a surgery condition) and observed no changes in either the production of amyloid-beta protein or the rate of cell death. However, when combined with low oxygen levels (18%), desflurane could stimulate these cellular changes associated with Alzheimer's (hypoxia by itself did not induce any changes). The results with desflurane are contrary to the researchers' previous work, which found isoflurane by itself could stimulate both amyloid production and cell death.

The researchers do emphasize that the current findings are from cell culture experiments, and the next critical step will be to confirm these findings in animal models and test the effects of other anesthetic agents. But, these early results suggest that it is important to ensure anesthetic patients maintain sufficient oxygen in their brain. http://www.medicalnewstoday.com .

Study supports lycopene protecting skin from within
Consuming lycopene-rich tomato paste may protect against sunburn and sun-induced skin ageing, British researchers have reported. http://www.nutraingredients.com

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A novel strategy for therapeutic intervention in Alzheimer's

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JADO Technologies GmbH, the leading developer of RAFT intervention therapeutics, has announced he publication of a paper in Science demonstrating a potential novel strategy for therapeutic intervention in Alzheimer's and other diseases by targeting discrete sub-compartments in the cell membrane (RAFTS). The study conducted by JADO scientists together with several academic collaborators will appear in the April 25, 2008 issue of the magazine.

Entitled "Efficient inhibition of the Alzheimer's disease ß-secretase by membrane targeting", the paper describes how ß-secretase, the rate-limiting enzyme in the production of Alzheimer's disease associated ß-amyloid peptide, can be inhibited effectively using compounds anchored to cell membrane RAFTS. Unlike existing approaches for ß-secretase inhibition that do not account for the intracellular location of the target protein or the different conformation that the protein may assume in this context, these RAFT inhibitors are delivered to the exact site where ß-secretase executes its neurotoxic activity.

"Our data provide proof-of principle of a new approach for directing small molecule inhibitors to disease causing RAFT targets in cellular membranes. In this instance, by directing inhibition to the sub-compartment where the enzyme is active, the approach has potential to be used in the design of more effective β-secretase inhibitors for the treatment of Alzheimer's disease," noted Professor Kai Simons, Max-Planck Institute of Molecular Cell Biology and Genetics and co-founder of JADO. "We believe that this novel strategy can be used to design therapeutics against other RAFT targets in a range of other diseases."

ß-secretase is internalized from the cell membrane into intracellular compartments (endosomes) where it cleaves its substrate, Amyloid Precursor Protein (APP). Most soluble inhibitors of ß-secretase do not gain access to this internal location, so the researchers first tested whether anchoring of such a ß-secretase inhibitor to the membrane would confer inhibitory activity upon it by bringing it to the right compartment. A peptide inhibitor of ß-secretase, which inhibited soluble ß-secretase but failed to block the enzyme in a cellular assay, was coupled to a sterol anchor molecule and a potent inhibition of ß-secretase activity demonstrated. Concentrations as low as 100 nM of the anchored inhibitor were sufficient to completely block appearance of amyloid peptide. In an animal model of Alzheimer's disease, the same sterol-coupled inhibitor reduced ß-amyloid formation in the brain by 50% over 4 hours, whereas the free inhibitor was ineffective.

The researchers explained that the advantage of using a sterol anchor was to target and increase the concentration of the inhibitor in the sterol-rich RAFT domains where ß-secretase cleaves APP. Evidence was also provided that the RAFT anchor could not be substituted by any other lipid type and that knowledge of RAFT chemistry is crucial. http://www.medicalnewstoday.com .

Micronutrients show potential against TB recurrence

Daily supplements of micronutrients vitamins A, B-complex, C, E, and selenium may reduce the recurrence of tuberculosis during standard treatment, suggests a new study.

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Early life experiences contribute to amyloidogenesis

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Alzheimer's Disease (AD) is a progressive, irreversible neurodegenerative disease. Despite several genetic mutations (Haass et al., J. Biol. Chem. 269:17741-17748, 1994; Ancolio et al., Proc. Natl. Acad. Sci. USA 96:4119-4124, 1999; Munoz and Feldman, CMAJ 162:65-72, 2000; Gatz et al., Neurobiol. Aging 26:439-447, 2005) found in AD patients, more than 90% of AD cases are sporadic (Bertram and Tanzi, Hum. Mol. Genet. 13:R135-R141, 2004). Therefore, it is plausible that environmental exposure may be an etiologic factor in the pathogenesis of AD. The AD brain is characterized by extracellular beta-amyloid (Abeta) deposition and intracellular hyperphosphorylated tau protein. Our lab has demonstrated that developmental exposure of rodents to the heavy metal lead (Pb) increases APP (amyloid precursor protein) and Abeta production later in the aging brain (Basha et al., J. Neurosci. 25:823-829, 2005a). We also found elevations in the oxidative marker 8-oxo-dG in older animals that had been developmentally exposed to Pb (Bolin et al., FASEB J. 20:788-790, 2006) as well as promotion of amyloidogenic histopathology in primates. These findings indicate that early life experiences contribute to amyloidogenesis in old age perhaps through epigenetic pathways. Here we explore the role of epigenetics as the underlying mechanism that mediates this early exposure-latent pathogenesis with a special emphasis on alterations in the methylation profiles of CpG dinucleotides in the promoters of genes and their influence on both gene transcription and oxidative DNA damage. J Mol Neurosci. 2008;34(1):1-7

Can flavonoid-rich chocolate protect against heart disease?
A study to be conducted by the University of East Anglia (UEA), UK, will examine whether adding flavonoids found in cocoa to the diet, gives additional protection against heart disease on top of that provided by prescription drugs. http://www.nutraingredients.com
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Alzheimer's has different effects in different racial and ethnic groups

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Hispanic and black caregivers are more likely than other ethnic groups to misinterpret symptoms of Alzheimer's disease as normal signs of aging, according to a recent survey by the Alzheimer's Foundation of America, HealthDay/Washington Post reports. The survey found that 37% of black caregivers and 33% of Hispanic caregivers believed that the disease's symptoms were a normal part of aging, compared with 23% of caregivers from other racial or ethnic groups. The survey also found that black and Hispanic caregivers were more likely to report that they knew little about Alzheimer's.

Misinterpretation of the disease's symptoms "often leads to delays in seeking care, when early treatment might make a difference in the progression" of the condition, HealthDay/Post reports. Experts said the survey's findings indicate a need for more culturally competent education on Alzheimer's disease. Eric Hall, founding CEO of AFA, called the findings "distressing," adding, "In the absence of a cure, care becomes a critical issue to sustain the highest quality of life for the longest time."

According to Angela Geiger, vice president of constituent relations for the Alzheimer's Association, Alzheimer's has different effects in different racial and ethnic groups. For example, the disease is more prevalent in blacks than whites, and Hispanics are more likely to display symptoms earlier. Such differences prompted the organization to create "a series of culturally appropriate publications tailored" to blacks and Hispanics, she said (Doheny, HealthDay/Washington Post, 4/20). http://www.medicalnewstoday.com .

Croda kick starts UK brain food scheme
Croda has become the first ingredient supplier to receive accreditation under UK charity Food for the Brain Foundation's new labelling scheme that recognises products with cognitive benefits.http://www.nutraingredients.com

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Transforming dementia services in Scotland

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Today's Ministerial statement on dementia by Shona Robison MSP is warmly welcomed by Alzheimer Scotland. It confirms that the Scottish Government recognises the scale of the problem of dementia in Scotland, as highlighted by our recent report The Dementia Epidemic - where Scotland is now and the challenge ahead.

The programme has identified the need for changes in service provision for people with dementia across Scotland, including the integration of palliative care as promoted by Scotland's Beyond Barriers project. It also recognises the need to enhance the research into dementia, its causes and potential treatments; a need that has received much attention following the recent comments of Terry Pratchett. Awareness raising and information sharing will be promoted, increasing the understanding of dementia across Scotland. All this gievs substance to the Scottish Government's commitment to making dementia a national priority.

In addition, the announcement of joint funding of £600,000 (over three years) between Alzheimer Scotland and the Dementia Services Development Centre in Stirling will allow the organisation to carry out invaluable work on post-diagnostic support and information initiatives for people with dementia and their carers.

Jim Jackson, Chief Executive at Alzheimer Scotland, said, "This is an important start to work which needs to be done by the Government, NHS, local authorities, voluntary and private sector services. As more people are diagnosed, Scotland will need to be better prepared to provide personalised support for people with dementia. We look forward to working with our partners in the Dementia Forum and transforming dementia services in Scotland." http://www.medicalnewstoday.com .

Vitamin D, calcium combo may cut exercise-related stress fractures

Daily supplements of calcium and vitamin D, long linked to improving bone health, may also reduce the risk of stress fractures during exercise, scientists have reported.

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Breakthrough in the research into the cause of Alzheimer's

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According to estimates there are 85,000 Alzheimer patients in our country and approximately 20,000 new cases every year. This spectacular increase is due to the increasing ageing population. Unfortunately it is still unclear precisely which ageing process forms the basis of this spectacular rise in the occurrence of the disease. VIB scientists affiliated to K.U.Leuven have discovered an important molecular link between Alzheimer's disease and the development of the typical plaques in the brains of Alzheimer patients. This discovery is an important breakthrough in the fundamental research into the cause of Alzheimer's disease.

Alzheimer's disease, a neurodegenerative disease that slowly and gradually destroys brain cells, is the most common form of dementia in the Western world. The way in which it affects the memory and mental functioning makes it one of the most frightening disorders. Over the last 15 years the amount of research worldwide into this still incurable disease has grown considerably: faster diagnosis of the disease and better treatment are essential. Alzheimer's disease is associated with amyloid plaques i.e. abnormal accumulations of protein fragments that form in the brain cells. A few years ago Bart De Strooper and other researchers unravelled the process by which these plaques develop in the familial form of Alzheimer's disease (less common form). ?-secretase, which cuts proteins at a specific location plays an important role here. Sometimes the secretase cuts in the wrong place, which results in a by-product and thus the formation of plaques. In the most common form of the disorder the same sort of plaques are found, but there is still little known about their development mechanism

In patients with the most common form of Alzheimer's disease the brain cells show an increase in the protein BACE1 or ß-secretase. VIB researcher Sébastien Hébert and colleagues, under the direction of Bart De Strooper and in collaboration with international experts, looked into the cause of this increase. To this end the VIB researchers checked the expression profiles of certain microRNA's, i.e. the short pieces of RNA that regulate protein production. In patients where there was an increase in the BACE1 protein, there was a significant reduction in miR-29a and miR-29b-1. This observation suggests the possible role of certain miRNA's in the increase of BACE1 and in the formation of plaques in the brains of patients with Alzheimer's disease.

On the one hand this research raises hopes for a better diagnostic test. Timely prescription of certain medicines for Alzheimer's disease results after all in a better response, and thus a better quality of life for the patient. On the other hand there is the question of whether these microRNA's could in the future form the basis of a new drug. http://www.medicalnewstoday.com .

Lifelong prebiotic supplements may enhance survival: rat study
Lifelong supplementation with the prebiotics inulin and oligofructose may extend lifespan by over 30 per cent, according to a new animal study from France. http://www.nutraingredients.com

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Immune Globulin Intravenous for the treatment of Alzheimer's

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Presbyterian Hospital/Weill Cornell Medical Center and Baxter International Inc. (NYSE: BAX) announced results of a six-month, placebo-controlled Phase II study of 24 patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID [Immune Globulin Intravenous (IGIV)] for the treatment of mild-to-moderate Alzheimer's disease today at the American Academy of Neurology (AAN) annual meeting in Chicago. The study met the primary endpoint criteria favoring GAMMAGARD LIQUID and GAMMAGARD S/D over placebo on measures of cognitive function and global impression of change, which are common measures of outcome in Alzheimer's disease clinical trials. The study also met secondary endpoints that measured changes in beta-amyloid and anti-amyloid antibody levels in blood and cerebrospinal fluid. Results show findings indicative of potential efficacy and tolerability. Key findings throughout six months included: measurements of clinical outcome, behavioral outcome and cognitive performance in Alzheimer's patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID compared to placebo. Twelve-to-18 month data will be available later this year.

Secondary endpoint results suggest that levels of antibodies against beta-amyloid were observed to have increased in the blood and cerebrospinal fluid of patients treated with GAMMAGARD S/D and GAMMAGARD LIQUID, while the levels of beta-amyloid increased in the blood. Beta-amyloid is a substance thought to contribute to the degeneration of the brain in Alzheimer's disease. Clearing this substance from the central nervous system, therefore is hypothesized to help remove or reduce the building blocks of Alzheimer's.

The primary and secondary endpoint data were reported by the lead researcher for the trial, Dr. Norman Relkin, director of the Memory Disorders Program and behavioral neurologist and neuroscientist at New York-Presbyterian/Weill Cornell Medical Center, and associate professor of clinical neurology at Weill Cornell Medical College in New York City. "This was the first placebo-controlled clinical trial of GAMMAGARD for Alzheimer's disease and the results are clearly promising," Dr. Relkin commented. Baxter supported the study and provided GAMMAGARD LIQUID and GAMMAGARD S/D for the trial. GAMMAGARD S/D and GAMMAGARD LIQUID, marketed as KIOVIG in the European Union, contain a broad spectrum of immunoglobulins (antibodies) and are indicated as an immunoglobulin replacement therapy that boosts the immune system in patients with primary immunodeficiency disorders. The precise mechanisms of GAMMAGARD S/D and GAMMAGARD LIQUID's effects in Alzheimer's disease are not known. "These study results reflect Baxter's support of innovative science and commitment to meeting a critical, unmet medical need," said Hartmut J. Ehrlich, MD, vice president of global research and development for Baxter's BioScience business. "While results of Baxter's mid-stage development work in Alzheimer's disease treatment are promising, further investigation in a larger Phase III study is required." http://www.medicalnewstoday.com .

Season lightly for nutrient-rich tomatoes
Differences between salt and fresh water organisms does not usually extend to land plants, but Italian researchers report that watering tomatoes with diluted seawater can boost their nutrient content. http://www.nutraingredients.com

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Heavy drinkers developed Alzheimer's 4.8 years earlier

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Heavy drinkers and heavy smokers develop Alzheimer's disease years earlier than people with Alzheimer's who do not drink or smoke heavily, according to research that will be presented at the American Academy of Neurology 60th Anniversary Annual Meeting in Chicago, April 12-19, 2008.

"These results are significant because it's possible that if we can reduce or eliminate heavy smoking and drinking, we could substantially delay the onset of Alzheimer's disease for people and reduce the number of people who have Alzheimer's at any point in time," said study author Ranjan Duara, MD, of the Wien Center for Alzheimer's Disease at Mount Sinai Medical Center in Miami Beach, FL, and Fellow of the American Academy of Neurology.

"It has been projected that a delay in the onset of the disease by five years would lead to a nearly 50-percent reduction in the total number of Alzheimer's cases," said Duara. "In this study, we found that the combination of heavy drinking and heavy smoking reduced the age of onset of Alzheimer's disease by six to seven years, making these two factors among the most important preventable risk factors for Alzheimer's disease."

The study looked at 938 people age 60 and older who were diagnosed with possible or probable Alzheimer's disease. The researchers gathered information from family members on drinking and smoking history and determined whether the participants had the epsilon 4 gene variant of the APOE gene, which increases the risk of Alzheimer's disease. People with the epsilon 4 variant also develop Alzheimer's at an earlier age than those who do not have the gene variant.

Seven percent of the study participants had a history of heavy drinking, which was defined as more than two drinks per day. Twenty percent had a history of heavy smoking, which was defined as smoking one pack of cigarettes or more per day. And 27 percent had the APOE epsilon 4 variant.

Researchers found that people who were heavy drinkers developed Alzheimer's 4.8 years earlier than those who were not heavy drinkers. Heavy smokers developed the disease 2.3 years sooner than people who were not heavy smokers. People with APOE epsilon 4 developed the disease three years sooner than those without the gene variant.

Adding the risk factors together led to earlier onset of the disease. People who had all three risk factors developed the disease 8.5 years earlier than those with none of the risk factors. The 17 people in the study with all three risk factors developed Alzheimer's at an average age of 68.5 years; the 374 people with none of the three risk factors developed the disease at an average age of 77 years. http://www.medicalnewstoday.com .

Vitamin D pills for risk groups may be warranted
The benefits of vitamin D for brain health may warrant recommendations for supplements in groups at risk of low levels, leading American scientists say. http://www.nutraingredients.com

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