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Specific Extra Phosphate on Tau Protein Crucial to Alzheimer’s Disease

Scientists have shown that a particular one of the multiple extra phosphates on the abnormal tau protein in Alzheimer’s disease appears to be a principal cause of the disease. "The impact of this study is twofold," said Dr. Hemant Paudel, the senior author of the study. "We can now do brain imaging at the earliest stages of the disease. We don't have to look for many different tau phosphates, just this single phosphate. The possibility of early diagnosis now exists. Second, the enzyme which puts this phosphate on the tau can be targeted by drugs, so therapies can be developed. This discovery gives us, for the first time, a clear direction towards the early diagnosis and treatment of Alzheimer's." Several years ago, it was discovered that tau proteins in normal brains contain only three to four attached phosphates, while abnormal tau proteins in Alzheimer's patients have anywhere from 21 to 25 additional phosphates. Here, Dr. Paudel and his team have shown that the addition of a single phosphate to the serine 202 amino acid within the tau protein is a likely principal culprit in Alzheimer's disease. This work was published in the May 15 issue of the Journal of Biological Chemistry. [Press release] [JBC abstract]

Increased Flu Susceptibility Associated with Arsenic in Well Water—Possible Mexico Connection

Susceptibility to influenza A (H1N1) infection is significantly increased by exposure to low levels of arsenic commonly encountered in contaminated well water. This is the conclusion of researchers who studied the effects of low levels of arsenic in the drinking water of mice. The initial immune response of these mice to influenza A (H1N1) was quite feeble and when the response was made it was too robust and too late. "There was a massive infiltration of immune cells to the lungs and a massive inflammatory response, which led to bleeding and damage in the lung," said Dr. Joshua Hamilton, an author of the study. Morbidity over the course of the infection was significantly higher for the arsenic-exposed mice than for the normal mice. The U.S. Environmental Protection Agency considers 10 parts per billion (ppb) arsenic in drinking water "safe," yet concentrations of 100 ppb and higher are commonly found in well water in regions where arsenic is geologically abundant, including upper New England (Massachusetts, New Hampshire, Maine), Florida, and large parts of the Upper Midwest, the Southwest, and the Rocky Mountains. Respiratory infections with influenza A virus are a worldwide health concern and are responsible for 36,000 deaths annually. The recent outbreak of the influenza A H1N1 substrain ("swine flu"), which is the same virus used in this study, has, to date, killed 72 people in Mexico and 6 in the United States. "One thing that did strike us, when we heard about the recent H1N1 outbreak, is Mexico has large areas of very high arsenic in their well water, including the areas where the flu first cropped up. We don't know that the Mexicans who got the flu were drinking high levels of arsenic, but it's an intriguing notion that this may have contributed," Dr. Hamilton said.

Cancer Drugs May Be Useful in Treating Alcoholism

Discovery and functional analysis of a mutant gene (“happyhour”) in fruit flies has led researchers to suggest that certain existing cancer drugs may be effective in treating alcoholism. The mutant “happyhour” gene increases the resistance of the fruit flies to the sedative effects of alcohol. This is similar to the situation in humans where such increased resistance is thought to contribute to the development of alcohol addiction. Studies have indicated that an individual's sensitivity to alcohol intoxication acts as a predictor of future alcoholism, with a link between lower initial response and increased risk of addiction. Here, the researchers showed that the epidermal growth factor (EGF) signaling pathway regulates the fruit fly’s sensitivity to alcohol, and that the normal “happyhour” protein functions as an inhibitor of this pathway. The EGF pathway is best known for its role in cancer, and drugs designed to inhibit the EGF receptor (EGFR), including erlotinib (trade name Tarceva) and gefitinib (trade name Iressa), are FDA-approved for the treatment of non-small cell lung cancer. Here, the researchers showed that fruit flies and mice treated with erlotinib also grow more sensitive to alcohol. In addition, rats given the cancer-fighting drug spontaneously consumed less alcohol when it was freely available to them. The authors concluded that inhibitors of EGFR or components of its signaling pathway are potential pharmacotherapies for alcohol addiction. This work was published in the May 21 online edition of Cell. [Press release] [Cell abstract]

Anti-Angiogenesis Genes May Contribute to Low Cancer Rate in Down Syndrome

Researchers have provided evidence that the extra copies of two chromosome 21 genes may be responsible, at least in part, for the extremely low cancer rate in those with Down syndrome. The rate of cancer in Down syndrome individuals is lower than 10 percent of that in the general population. It had been proposed that because Down syndrome individuals have an extra copy of chromosome 21, that there may be one or more cancer-protective genes on this chromosome. The late cancer researcher Dr. Judah Folkman proposed that the extra copy of chromosome 21 may contain a gene that blocks angiogenesis, the development of blood vessels essential for cancer's growth. In the current experiments, scientists showed that a single extra copy of the chromosome 21 gene Dscr1 is sufficient to significantly suppress angiogenesis and tumor growth in mice, as well as angiogenesis in human cells. The team also found that levels of DSCR1 protein are elevated in tissues from people with Down syndrome and in a mouse model of the disease. The extra copy of another chromosome 21 gene, Dyrk1A, also appeared to decrease cells' response to an angiogenesis-promoting protein. "I think there may be four or five genes on chromosome 21 that are necessary for angiogenesis suppression," said Dr. Sandra Ryeom, the senior author of the report. "In huge databases of cancer patients with solid tumors, there are very few with Down syndrome. This suggests that protection from chromosome 21 genes is pretty complete." This research was published online on May 20 in Nature. [Press release] [Nature abstract]

Sweet Tooth May Be Achilles Heel of Salmonella

Scientists have shown that the Salmonella food poisoning bacterium requires glucose as a nutrient during infection, and that when it is unable to use this nutrient, infection is prevented. "This is the first time that anyone has identified the nutrients that sustain Salmonella while it is infecting a host's body," says Dr Arthur Thompson, the senior author of the report. Salmonella food poisoning causes infection in approximately 20 million people worldwide each year and is responsible for about 200,000 human deaths. It also infects farm animals and attaches to salad vegetables. During infection, Salmonella bacteria are engulfed by immune cells designed to kill them. Instead, however, the bacteria multiply. The scientists constructed Salmonella mutants unable to transport glucose into the immune cells they occupy and unable to use glucose as food. These mutant strains lost their ability to replicate within the immune cells, rendering them harmless. The mutant strains still stimulate the immune system, and the scientists have filed patents on these mutant strains which could be used to develop vaccines to protect people and animals against poisoning by fully virulent Salmonella. This work was published in the April 20 issue of Infection and Immunity. [Press release]

Atrial Fibrillation A Predictor for Alzheimer’s Disease

Patients under the age of 70 with atrial fibrillation are 130 percent more likely to develop Alzheimer’s disease than those without the heart disease, according to a recent study. "Previous studies have shown that patients with atrial fibrillation are at higher risk for some types of dementia, including vascular dementia. But to our knowledge, this is the first large-population study to clearly show that having atrial fibrillation puts patients at greater risk for developing Alzheimer's disease," said Dr. T. Jared Bunch, the study’s lead researcher. Atrial fibrillation is the most common heart rhythm problem, affecting about 2.2 million Americans. It occurs when the heart beats chaotically, leading blood to pool and possibly clot. If the clot leaves the heart, a stroke can result. "Now that we've established this link, our focus will be to see if early treatment of atrial fibrillation can prevent dementia or the development of Alzheimer's disease," said Dr. John Day, a co-author of the study. The work was presented on May 15 during the annual scientific sessions of the Heart Rhythm Society. [Press release]

Gateway to Brain in Bacterial Meningitis Is Discovered

Scientists have discovered a key common mechanism in the pathology of bacterial meningitis, a disease that can cause death within hours of the appearance of symptoms. The researchers have shown that the three bacteria most commonly associated with childhood bacterial meningitis—Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenzae—all target the same receptor (the laminin receptor) in the special filtering system (the vascular endothelium) that helps form the blood-brain barrier. This interaction allows the bacteria to pass through the barrier and enter the brain. The researchers suggested that disruption or modulation of the interaction of bacterial adhesins with the barrier receptor might offer unexpectedly broad protection against bacterial meningitis and might provide a therapeutic target for the prevention and treatment of disease. This work was published on May 13 in the Journal of Clinical Investigation. [Press release] [Journal of Clinical Investigation article]

Coral Transcriptome Revealed

Using a new technique for cDNA preparation, combined with the latest sequencing methods, researchers have characterized the larval transcriptome of a reef-building coral (Acropora millepora). The research team identified approximately 11,000 genes on the basis of sequence similarity with known proteins, over 30,000 markers of genetic variation, and a number of novel candidate genes for stress-related processes. The characterization of the larval transcriptome for this widely studied coral will enable research into the biological processes underlying stress responses in corals and their evolutionary adaptation to global climate change. This work was published in BMC Genomics. [Press release] [BMC Genomics article]

Protective Gene Variant Identified for Lou Gehrig’s Disease

A gene variant that extends the survival time in amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, by as much as 50 percent has been identified by an international team of researchers. "This report is the first to describe genetic factors that determine rate of progression in ALS," said Dr. Robert Brown, one of the study leaders. The gene is KIFAP3 and researchers know that it is involved in a number of cellular processes, including the transport of essential molecules throughout the nerve cell. "The favorable gene variant decreases levels of a motor protein complex in nerves," said Dr. John Landers, also a leader of the study. "This complex transports substances through different parts of nerve cells. If we can understand the biological basis for the beneficial effect in ALS, it will potentially provide a target for the development of new ALS treatments.” Because survival with ALS is normally only three to five years, patients with the KIFAP3 gene variant experience a substantial improvement. In fact, the researchers suggested that impact of this genetic variant is comparable to the effect of the only drug (Riluzole) now approved for use in ALS in the United States. More importantly, this genetic variant may potentially point the way to future drug development efforts. This work is reported in PNAS. [Press release]

Novel Potassium Channel Implicated in Schizophrenia

Expression of a previously unknown, primate-specific, and brain-specific isoform (3.1) of a key potassium channel protein (KCNH2) that modulates neuronal firing was found to be 2.5-fold higher than normal in the hippocampus (brain memory hub) of people with schizophrenia, especially in those with schizophrenia risk-associated variations in the KCNH2 gene, according to a recent report. KCNH2-3.1 isoform levels were also found to be higher than normal in healthy individuals who carried the risk-associated KCNH2 gene variations, and these individuals were shown to exhibit some schizophrenia-like effects in brain circuitry and mental processing, even though they do not show psychotic behavior. "Our study goes further [than gene association studies], spanning discovery of a new gene variant, confirmation of its association with the illness, and multi-level probes into how it works--in human post-mortem brain tissue, the living human brain, and neurons," said Dr. Daniel Weinberger, director of the National Institute of Mental Health's Genes Cognition and Psychosis Program. An extensive series of experiments suggest that selectively inhibiting the KCNH2-3.1 isoform could help correct disorganized brain activity in schizophrenia, without risk of the cardiac side effects associated with some existing antipsychotic medications. This work was reported in the May issue of Nature Medicine. [NIH release] [Nature Medicine abstract]

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