Posts tagged alzheimer
Articles and news from the latest research reports.
Specific Antibodies Halt Alzheimer’s Disease in Mice
ScienceDaily (Mar. 6, 2012) — Antibodies that block the process of synapse disintegration in Alzheimer’s disease have been identified, raising hopes for a treatment to combat early cognitive decline in the disease.
Amyloid beta (cyan blue) binds to nerve cells of the hippocampus (red) and attacks synapses resulting in the loss of memories in Alzheimer’s disease. New research has led to important insights into the mechanisms that induce synapse loss. The discovery brings hope for the development of new therapies that protect synapses and therefore prevent memory loss in Alzheimer’s disease. (Credit: Silvia Purro/Patricia Salinas/UCL)
Alzheimer’s disease is characterized by abnormal deposits in the brain of the protein Amyloid-ß, which induces the loss of connections between neurons, called synapses.
Now, scientists at UCL have discovered that specific antibodies that block the function of a related protein, called Dkk1, are able to completely suppress the toxic effect of Amyloid-ß on synapses. The findings are published March 6 in the Journal of Neuroscience.
Professor Patricia Salinas (UCL Department of Cell & Developmental Biology) who led the study, said: “These novel findings raise the possibility that targeting this secreted Dkk1 protein could offer an effective treatment to protect synapses against the toxic effect of Amyloid-ß.
"Importantly, these results raise the hope for a treatment and perhaps the prevention of cognitive decline early in Alzheimer’s disease."
Laboratory research shows promising approach to preventing Alzheimer’s
(Medical Xpress) — As scientists struggle to find an effective way to prevent Alzheimer’s disease, researchers at the University of Wisconsin School of Medicine and Public health may have found a new approach to interrupting the process that leads to the devastating disease.
The image shows that the enzymes ATase1 and ATase2 are abundantly present in the brains of Alzheimer’s disease patients. The green color labels the ATases while the blue labels the nuclei. Both neurons and glial cells are shown.
Building on their knowledge of two enzymes that control an “uber” enzyme critical to the development of the disease, the scientists found that the two enzymes are present in the brains of Alzheimer’s patients. And by screening some 15,000 compounds, they discovered two that lower activity of the enzymes in test tubes.
How Anesthetic Isoflurane Induces Alzheimer’s-Like Changes in Mammalian Brains
ScienceDaily (Mar. 1, 2012) — The association of the inhaled anesthetic isoflurane with Alzheimer’s-disease-like changes in mammalian brains may by caused by the drug’s effects on mitochondria, the structures in which most cellular energy is produced. In a study that will appear in Annals of Neurology and has received early online release, Massachusetts General Hospital (MGH) researchers report that administration of isoflurane impaired the performance of mice on a standard test of learning and memory — a result not seen when another anesthetic, desflurane, was administered. They also found evidence that the two drugs have significantly different effects on mitochondrial function.
"These are the first results indicating that isoflurane, but not desflurane, may induce neuronal cell death and impair learning and memory by damaging mitochondria," says Yiying (Laura) Zhang, MD, a research fellow in the MGH Department of Anesthesia, Critical Care and Pain Medicine and the study’s lead author. "This work needs to be confirmed in human studies, but it’s looking like desflurane may be a better anesthetic to use for patients susceptible to cognitive dysfunction, such as Alzheimer’s patients."
Previous studies have suggested that undergoing surgery and general anesthesia may increase the risk of Alzheimer’s, and it is well known that a small but significant number of surgical patients experience a transient form of cognitive dysfunction in the postoperative period. In 2008, members of the same MGH research team showed that isoflurane induced Alzheimer’s-like changes — increasing activation of enzymes involved with cell death and generation of the A-beta plaques characteristic of the disease — in the brains of mice. The current study was designed to explore the underlying mechanism and behavioral consequences of isoflurane-induced brain cell death and to compare isoflurane’s effects with those of desflurane, another common anesthetic that has not been associated with neuronal damage.
In a series of experiments, the investigators found that the application of isoflurane to cultured cells and mouse neurons increased the permeability of mitochondrial membranes; interfered with the balance of ions on either side of the mitochondrial membrane; reduced levels of ATP, the enzyme produced by mitochondria that powers most cellular processes; and increased levels of the cell-death enzyme caspase. The results also suggested that the first step toward isoflurane-induced cell death was increased generation of reactive oxygen species — unstable oxygen-containing molecules that can damage cellular components. The performance of mice on a standard behavioral test of learning and memory declined significantly two to seven days after administration of isoflurane, compared with the results of a control group. None of the cellular or behavioral effects of isoflurane were seen when the administered agent was desflurane.
In another study by members of the same research team — appearing in the February issue of Anesthesia and Analgesia and published online in November — about a quarter of surgical patients receiving isoflurane showed some level of cognitive dysfunction a week after surgery, while patients receiving desflurane or spinal anesthesia had no decline in cognitive performance. That study, conducted in collaboration with investigators from Beijing Friendship Hospital in China, enrolled only 45 patients — 15 in each treatment group — so its results need to be confirmed in significantly larger groups.
"Approximately 8.5 million Alzheimer’s disease patients worldwide will need anesthesia and surgical care every year," notes Zhongcong Xie, MD, PhD, corresponding author of both studies and director of the Geriatric Anesthesia Research Unit in the MGH Department of Anesthesia, Critical Care and Pain Medicine. "Developing guidelines for safer anesthesia care for these patients will require collaboration between specialists in anesthesia, neurology, geriatric medicine and other specialties. As the first step, we need to identify anesthetics that are less likely to contribute to Alzheimer’s disease neuropathogenesis and cognitive dysfunction." Xie is an associate professor of Anesthesia at Harvard Medical School (HMS)
Source: Science Daily
Understanding and Treating the Cognitive Dysfunction of Down Syndrome and Alzheimer’s Disease
ScienceDaily (Mar. 1, 2012) — Down syndrome (DS) is the most common genetic disorder in live born children arising as a consequence of a chromosomal abnormality. It occurs as a result of having three copies of chromosome 21, instead of the usual two. It causes substantial physical and behavioral abnormalities, including life-long cognitive dysfunction that can range from mild to severe but which further deteriorates as individuals with DS age.
It is not currently possible to effectively treat the cognitive impairments associated with DS. However, these deficits are an increasing focus of research. In this issue of Biological Psychiatry, researchers at Stanford University, led by Dr. Ahmad Salehi, have published a review which highlights potential strategies for the treatment of these cognitive deficits.
The authors focus on insights emerging from animal models of Down syndrome and outline the structural abnormalities in the DS brain. They also discuss studies that have linked the over-expression of the amyloid precursor protein gene, called APP, to the degeneration of neurons in mice. These findings have led to the development of therapeutic treatments in mice, which now must be tested in humans.
"For more than a decade, we have been working on identifying a strategy to treat cognitive disabilities in our Down syndrome mouse models," said Dr. Salehi. "Considering the research and results with mouse models as an indication of success of a strategy in humans, we are ever closer to finding ways to at least partially restore cognitive function in children and adults with Down syndrome."
Interestingly, this research is also providing insights into Alzheimer’s disease (AD), the archetypal disorder of late life. All adults with Down syndrome develop AD pathology by age 40, and there are some remarkable similarities in the brain degeneration and cognitive dysfunction of individuals with DS and those with AD.
The leading AD hypothesis posits that it is caused by increasingly elevated levels of amyloid-related proteins, which are toxic to nerve cells in the brain. These same proteins also accumulate in the brains of people with DS because they are made by the APP gene, which is located on chromosome 21. Individuals with AD don’t have the extra chromosome, of course; rather, it is mutations in APP that appear to cause the brain degeneration associated with AD.
Dr. John Krystal, editor of Biological Psychiatry, commented: “The convergence of research on Down syndrome and Alzheimer’s disease highlights a central point that cannot be overstated. When we understand the fundamental biology of the brain, important new conceptual bridges emerge that guide new treatment approaches.”
Salehi added, “In the near future, we may very likely look back with the perspective that Down syndrome represents an example of how families of affected individuals came together and by supporting basic research, changed the course of a disorder that was considered untreatable for more than a century.”
Source: Science Daily
Blockade of Learning and Memory Genes May Occur Early in Alzheimer’s Disease: Treatable in Mice
ScienceDaily (Feb. 29, 2012) — A repression of gene activity in the brain appears to be an early event affecting people with Alzheimer’s disease, researchers funded by the National Institutes of Health have found. In mouse models of Alzheimer’s disease, this epigenetic blockade and its effects on memory were treatable.
In a mouse model of Alzheimer’s disease (right), HDAC2 levels in the hippocampus are higher than in the normal mouse hippocampus (left). Credit: (Credit: Dr. Li-Huei Tsai, MIT)
"These findings provide a glimpse of the brain shutting down the ability to form new memories gene by gene in Alzheimer’s disease, and offer hope that we may be able to counteract this process," said Roderick Corriveau, Ph.D., a program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research.
The study was led by Li-Huei Tsai, Ph.D., who is director of The Picower Institute for Learning and Memory at the Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute. It was published online February 29 in Nature.
Dr. Tsai and her team found that a protein called histone deacetylase 2 (HDAC2) accumulates in the brain early in the course of Alzheimer’s disease in mouse models and in people with the disease. HDAC2 is known to tighten up spools of DNA, effectively locking down the genes within and reducing their activity, or expression.
Reawakening Neurons: Researchers Find an Epigenetic Culprit in Memory Decline
ScienceDaily (Feb. 29, 2012) — In a mouse model of Alzheimer’s disease, memory problems stem from an overactive enzyme that shuts off genes related to neuron communication, a new study says.
When researchers genetically blocked the enzyme, called HDAC2, they ‘reawakened’ some of the neurons and restored the animals’ cognitive function. The results, published February 29, 2012, in the journal Nature, suggest that drugs that inhibit this particular enzyme would make good treatments for some of the most devastating effects of the incurable neurodegenerative disease.
"It’s going to be very important to develop selective chemical inhibitors against HDAC2," says Howard Hughes Medical Institute investigator Li-Huei Tsai, whose team at the Massachusetts Institute of Technology performed the experiments. "If we could delay the cognitive decline by a certain period of time, even six months or a year, that would be very significant."
In every cell, DNA wraps itself around proteins called histones. Chemical groups such as methyl and acetyl can bind to histones and affect DNA expression. HDAC2 is a histone deacetylase, an enzyme that removes acetyl groups from the histone, effectively turning off nearby genes.
Researchers Test Sugary Solution to Alzheimer’s Disease
ScienceDaily (Feb. 28, 2012) — Slowing or preventing the development of Alzheimer’s disease, a fatal brain condition expected to hit one in 85 people globally by 2050, may be as simple as ensuring a brain protein’s sugar levels are maintained.
Slowing or preventing the development of Alzheimer’s disease, a fatal brain condition expected to hit one in 85 people globally by 2050, may be as simple as ensuring a brain protein’s sugar levels are maintained. (Credit: © ktsdesign / Fotolia)
That’s the conclusion seven researchers, including David Vocadlo, a Simon Fraser University chemistry professor and Canada Research Chair in Chemical Glycobiology, make in the latest issue of Nature Chemical Biology.
The journal has published the researchers’ latest paper “Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation.”
Vocadlo and his colleagues describe how they’ve used an inhibitor they’ve chemically created — Thiamet-G — to stop O-GlcNAcase, a naturally occurring enzyme, from depleting the protein Tau of sugar molecules.
"The general thinking in science," says Vocadlo, "is that Tau stabilizes structures in the brain called microtubules. They are kind of like highways inside cells that allow cells to move things around."
Previous research has shown that the linkage of these sugar molecules to proteins, like Tau, in cells is essential. In fact, says Vocadlo, researchers have tried but failed to rear mice that don’t have these sugar molecules attached to proteins.
Vocadlo, an accomplished chess player in his spare time, is having great success checkmating troublesome enzymes with inhibitors he and his students are creating in the SFU chemistry department’s Laboratory of Chemical Glycobiology.
Research prior to Vocadlo’s has shown that clumps of Tau from an Alzheimer brain have almost none of this sugar attached to them, and O-GlcNAcase is the enzyme that is robbing them.
Such clumping is an early event in the development of Alzheimer’s and the number of clumps correlate with the disease’s severity.
Scott Yuzwa and Xiaoyang Shan, grad students in Vocadlo’s lab, found that Thiamet-G blocks O-GlcNAcase from removing sugars off Tau in mice that drank water with a daily dose of the inhibitor. Yuzwa and Shan are co-first authors on this paper.
The research team found that mice given the inhibitor had fewer clumps of Tau and maintained healthier brains.
"This work shows targeting the enzyme O-GlcNAcase with inhibitors is a new potential approach to treating Alzheimer’s," says Vocadlo. "This is vital since to date there are no treatments to slow its progression.
"A lot of effort is needed to tackle this disease and different approaches should be pursued to maximize the chance of successfully fighting it. In the short term, we need to develop better inhibitors of the enzyme and test them in mice. Once we have better inhibitors, they can be clinically tested.
Source: Science Daily
Turmeric-Based Drug Effective On Alzheimer Flies
ScienceDaily (Feb. 14, 2012) — Curcumin, a substance extracted from turmeric, prolongs life and enhances activity of fruit flies with a nervous disorder similar to Alzheimers, according to new research. The study conducted at Linköping University, indicates that it is the initial stages of fibril formation and fragments of the amyloid fibrils that are most toxic to neurons.
Above left are the survival curves for “Alzheimer flies” treated (dashed line) and those not treated with curcumin. The flies that were administered curcumin lived longer and were more active. The scientists identified an accelerated formation of amyloid plaque in the treated flies, which seemed to protect the nerve cells. On the right we see microscopic images of neurons (blue) and plaque (green) in the fruit fly’s brain. The study strengthens the hypothesis that a curcumin-based drug can contribute to toxic fibrils being encapsulated (bottom left of the figure). (Credit: Per Hammarström, Ina Caesar)
Ina Caesar, as the lead author, has published the results of the study in the journal PLoS ONE.
For several years curcumin has been studied as a possible drug candidate to combat Alzheimer’s disease, which is characterized by the accumulation of sticky amyloid-beta and Tau protein fibres. Linköping researchers wanted to investigate how the substance affected transgenic fruit flies (Drosophila melanogaster), which developed evident Alzheimer’s symptoms. The fruit fly is increasingly used as a model for neurodegenerative diseases.
Five groups of diseased flies with different genetic manipulations were administered curcumin. They lived up to 75 % longer and maintained their mobility longer than the sick flies that did not receive the substance.
However, the scientists saw no decrease of amyloid in the brain or eyes. Curcumin did not dissolve the amyloid plaque; on the contrary it accelerated the formation of fibres by reducing the amount of their precursor forms, known as oligomers.
"The results confirm our belief that it is the oligomers that are most harmful to the nerve cells," says Professor Per Hammarstrom, who led the study.
"We now see that small molecules in an animal model can influence the amyloid form. To our knowledge the encapsulation of oligomers is a new and exciting treatment strategy," he said.
Several theories have been established about how oligomers can instigate the disease process. According to one hypothesis, they become trapped at synapses, inhibiting nerve impulse signals. Others claim that they cause cell death by puncturing the cell membrane.
Curcumin is extracted from the root of herbaceous plant turmeric and has been used as medicine for thousands of years. More recently, it has been tested against pain, thrombosis and cancer.
Source: Science Daily
Flipping a Light Switch in the Cell: Quantum Dots Used for Targeted Neural Activation
February 9th, 2012
New technique holds promise for better understanding of brain disorders.
Quantum dot film. Optically excited quantum dots in close proximity to a cell control the opening of ion channels. Credit: Lugo et al., University of Washington.
Source: Neuroscience News
FDA-approved drug rapidly clears amyloid from the brain, reverses Alzheimer’s symptoms in mice
February 9, 2012
Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer’s disease. The researchers’ findings, published in the journal Science, show that use of a drug in mice appears to quickly reverse the pathological, cognitive and memory deficits caused by the onset of Alzheimer’s. The results point to the significant potential that the medication, bexarotene, has to help the roughly 5.4 million Americans suffering from the progressive brain disease.
Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer’s disease, and the results were more than promising.
Alzheimer’s disease arises in large part from the body’s inability to clear naturally-occurring amyloid beta from the brain. In 2008 Case Western Reserve researcher Gary Landreth, PhD, professor of neurosciences, discovered that the main cholesterol carrier in the brain, Apolipoprotein E (ApoE), facilitated the clearance of the amyloid beta proteins. Landreth, a professor of neurosciences in the university’s medical school, is the senior author of this study as well.
Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced.
In particular, the researchers were struck by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of Alzheimer’s disease. The present view of the scientific community is that small soluble forms of amyloid beta cause the memory impairments seen in animal models and humans with the disease. Within six hours of administering bexarotene, however, soluble amyloid levels fell by 25 percent; even more impressive, the effect lasted as long as three days. Finally, this shift was correlated with rapid improvement in a broad range of behaviors in three different mouse models of Alzheimer’s.
One example of the improved behaviors involved the typical nesting instinct of the mice. When Alzheimer’s-diseased mice encountered material suited for nesting – in this case, tissue paper – they did nothing to create a space to nest. This reaction demonstrated that they had lost the ability to associate the tissue paper with the opportunity to nest. Just 72 hours after the bexarotene treatment, however, the mice began to use the paper to make nests. Administration of the drug also improved the ability of the mice to sense and respond to odors.
Bexarotene treatment also worked quickly to stimulate the removal of amyloid plaques from the brain. The plaques are compacted aggregates of amyloid that form in the brain and are the pathological hallmark of Alzheimer’s disease. Researchers found that more than half of the plaques had been cleared within 72 hours. Ultimately, the reduction totaled 75 percent. It appears that the bexarotene reprogrammed the brain’s immune cells to “eat” or phagocytose the amyloid deposits. This observation demonstrated that the drug addresses the amount of both soluble and deposited forms of amyloid beta within the brain and reverses the pathological features of the disease in mice.
This study identifies a link between the primary genetic risk factor for Alzheimer’s disease and a potential therapy to address it. Humans have three forms of ApoE: ApoE2, ApoE3, and ApoE4. Possession of the ApoE4 gene greatly increases the likelihood of developing Alzheimer’s disease. Previously, the Landreth laboratory had shown that this form of ApoE was impaired in its ability of clear amyloid. The new work suggests that elevation of ApoE levels in the brain may be an effective therapeutic strategy to clear the forms of amyloid associated with impaired memory and cognition.
"This is an unprecedented finding," says Paige Cramer, PhD candidate at Case Western Reserve School of Medicine and first author of the study. "Previously, the best existing treatment for Alzheimer’s disease in mice required several months to reduce plaque in the brain."
Added Professor Landreth: “This is a particularly exciting and rewarding study because of the new science we have discovered and the potential promise of a therapy for Alzheimer’s disease. We need to be clear; the drug works quite well in mouse models of the disease. Our next objective is to ascertain if it acts similarly in humans. We are at an early stage in translating this basic science discovery into a treatment.”
Daniel Wesson, PhD, assistant professor of neurosciences at Case Western Reserve School of Medicine and co-author of the study agreed.
"Many often think of Alzheimer’s as a problem of remembering and learning, but the prevalent reality is this disease spreads throughout the brain, resulting in serious insults to numerous functions," he said. "The results of this study, showing the preservation of behaviors across a wide spectrum, and accompanying brain function, are tremendously exciting and suggest great promise in the utility of this approach in treatment of Alzheimer’s disease."
Bexarotene has a good safety and side-effect profile. The Case Western Reserve researchers hope these attributes will help speed the transition to clinical trials of the drug.
Professor Landreth said modest resources funded this self-described “far-fetched idea.” Crucial support came from the Blanchette Hooker Rockefeller Foundation, the Thome Foundation, and the National Institutes of Health.
Provided by Case Western Reserve University
Source: medicalxpress.com