Posts tagged alzheimer's disease
Articles and news from the latest research reports.
A third of a million adults in the UK are to be invited to take part in the world’s biggest study of cognitive function.
Study explores genetics behind Alzheimer’s resiliency
Autopsies have revealed that some individuals develop the cellular changes indicative of Alzheimer’s disease without ever showing clinical symptoms in their lifetime.
Vanderbilt University Medical Center memory researchers have discovered a potential genetic variant in these asymptomatic individuals that may make brains more resilient against Alzheimer’s.
“Most Alzheimer’s research is searching for genes that predict the disease, but we’re taking a different approach. We’re looking for genes that predict who among those with Alzheimer’s pathology will actually show clinical symptoms of the disease,” said principal investigator Timothy Hohman, Ph.D., a post-doctoral research fellow in the Center for Human Genetics Research and the Vanderbilt Memory and Alzheimer’s Center.
The article, “Genetic modification of the relationship between phosphorylated tau and neurodegeneration,” was published online recently in the journal Alzheimer’s and Dementia.
The researchers used a marker of Alzheimer’s disease found in cerebrospinal fluid called phosphorylated tau. In brain cells, tau is a protein that stabilizes the highways of cellular transport in neurons. In Alzheimer’s disease tau forms “tangles” that disrupt cellular messages.
Analyzing a sample of 700 subjects from the Alzheimer’s Disease Neuroimaging Initiative, Hohman and colleagues looked for genetic variants that modify the relationship between phosphorylated tau and lateral ventricle dilation — a measure of disease progression visible with magnetic resonance imaging (MRI). One genetic mutation (rs4728029) was found to relate to both ventricle dilation and cognition and is a marker of neuroinflammation.
“This gene marker appears to be related to an inflammatory response in the presence of phosphorylated tau,” Hohman said.
“It appears that certain individuals with a genetic predisposition toward a ‘bad’ neuroinflammatory response have neurodegeneration. But those with a genetic predisposition toward no inflammatory response, or a reduced one, are able to endure the pathology without marked neurodegeneration.”
Hohman hopes to expand the study to include a larger sample and investigate gene and protein expression using data from a large autopsy study of Alzheimer’s disease.
“The work highlights the possible mechanism behind asymptomatic Alzheimer’s disease, and with that mechanism we may be able to approach intervention from a new perspective. Future interventions may be able to activate these innate response systems that protect against developing Alzheimer’s symptoms,” Hohman said.
(Source: news.vanderbilt.edu)
Atypical Form of Alzheimer’s Disease May be Present in a More Widespread Number of Patients
Neuroscientists at Mayo Clinic in Florida have defined a subtype of Alzheimer’s disease (AD) that they say is neither well recognized nor treated appropriately.
The variant, called hippocampal sparing AD, made up 11 percent of the 1,821 AD-confirmed brains examined by Mayo Clinic researchers — suggesting this subtype is relatively widespread in the general population. The Alzheimer’s Association estimates that 5.2 million Americans are living with AD. And with nearly half of hippocampal sparing AD patients being misdiagnosed, this could mean that well over 600,000 Americans make up this AD variant, researchers say.
In an oral presentation at the annual meeting of the American Academy of Neurology in Philadelphia, scientists say hippocampal sparing AD often produces symptoms that are substantially different from the most commonly known form of AD, which affects the hippocampus, the center of memory.
The patients, mostly male, are afflicted at a much younger age, and their symptoms can be bizarre — behavioral problems such as frequent and sometimes profane angry outbursts, feelings that their limbs do not belong to them and are controlled by an “alien” unidentifiable force, or visual disturbances in the absence of eye problems, researchers say.
They also decline at a much faster rate than do patients with the most common form of AD.
“Many of these patients, however, have memories that are near normal, so clinicians often misdiagnose them with a variety of conditions that do not match the underlying neuropathology,” says the study’s lead author, Melissa Murray, Ph.D., an assistant professor of neuroscience at Mayo Clinic in Florida.
Many of these patients are diagnosed with frontotemporal dementia, a disorder characterized by changes in personality and social behavior, or corticobasal syndrome, characterized by movement disorders and cognitive dysfunction. Language dysfunction is also more common in hippocampal sparing AD, although patients do not have vocal or hearing deficits.
“What is tragic is that these patients are commonly misdiagnosed and we have new evidence that suggests drugs now on the market for AD could work best in these hippocampal sparing patients — possibly better than they work in the common form of the disease,” Dr. Murray says.
The researchers benefit greatly from one of the largest brain banks in the country — more than 6,500 brain donations — as well as a collaborative environment between neuroscience research and neurology at Mayo Clinic, she says.
Both hallmark proteins of AD — amyloid beta (Aβ), which forms Aβ plaques, and tau, which produces tangles — are found across all subtypes of AD, including hippocampal sparing AD. The researchers developed a mathematical algorithm to classify AD subtypes using tangle counts. “What is fascinating is that all the AD patient subtypes had the same amount of amyloid, but for some reason tau tangles were found in strategic cortical regions disproportionate to the hippocampus.”
In these patients, tau preferentially damages and eventually destroys neurons in parts of the brain involved in behavior, motor awareness and recognition, as well as use of speech and vision, Dr. Murray says.
She says she hopes this research, the second high-profile Mayo study to highlight hippocampal sparing AD, will “open the minds” of clinicians who are trying to diagnose dementia, helping them understand that loss of memory is not present in every AD patient.
“Our studies support the notion that dementia related to AD does not necessarily equate to a loss of memory, and points to the need for more research in amyloid and tau imaging biomarkers to help clinicians accurately diagnose AD — regardless of subtype,” Dr. Murray says.
(Source: newsnetwork.mayoclinic.org)
Exercise Keeps Hippocampus Healthy in People at Risk for Alzheimer’s
A study of older adults at increased risk for Alzheimer’s disease shows that moderate physical activity may protect brain health and stave off shrinkage of the hippocampus – the brain region responsible for memory and spatial orientation that is attacked first in Alzheimer’s disease. Dr. J. Carson Smith, a kinesiology researcher in the University of Maryland School of Public Health who conducted the study, says that while all of us will lose some brain volume as we age, those with an increased genetic risk for Alzheimer’s disease typically show greater hippocampal atrophy over time. The findings are published in the open-access journal Frontiers in Aging Neuroscience.
"The good news is that being physically active may offer protection from the neurodegeneration associated with genetic risk for Alzheimer’s disease," Dr. Smith suggests. "We found that physical activity has the potential to preserve the volume of the hippocampus in those with increased risk for Alzheimer’s disease, which means we can possibly delay cognitive decline and the onset of dementia symptoms in these individuals. Physical activity interventions may be especially potent and important for this group."
Dr. Smith and colleagues, including Dr. Stephen Rao from the Cleveland Clinic, tracked four groups of healthy older adults ages 65-89, who had normal cognitive abilities, over an 18-month period and measured the volume of their hippocampus (using structural magnetic resonance imaging, or MRI) at the beginning and end of that time period. The groups were classified both for low or high Alzheimer’s risk (based on the absence or presence of the apolipoprotein E epsilon 4 allele) and for low or high physical activity levels.
Of all four groups studied, only those at high genetic risk for Alzheimer’s who did not exercise experienced a decrease in hippocampal volume (3 percent) over the 18-month period. All other groups, including those at high risk for Alzheimer’s but who were physically active, maintained the volume of their hippocampus.
"This is the first study to look at how physical activity may impact the loss of hippocampal volume in people at genetic risk for Alzheimer’s disease," says Dr. Kirk Erickson, an associate professor of psychology at the University of Pittsburgh. "There are no other treatments shown to preserve hippocampal volume in those that may develop Alzheimer’s disease. This study has tremendous implications for how we may intervene, prior to the development of any dementia symptoms, in older adults who are at increased genetic risk for Alzheimer’s disease."
Individuals were classified as high risk for Alzheimer’s if a DNA test identified the presence of a genetic marker – having one or both of the apolipoprotein E-epsilon 4 allele (APOE-e4 allele) on chromosome 19 – which increases the risk of developing the disease. Physical activity levels were measured using a standardized survey, with low activity being two or fewer days/week of low intensity activity, and high activity being three or more days/week of moderate to vigorous activity.
"We know that the majority of people who carry the E4 allele will show substantial cognitive decline with age and may develop Alzheimer’s disease, but many will not. So, there is reason to believe that there are other genetic and lifestyle factors at work," Dr. Smith says. "Our study provides additional evidence that exercise plays a protective role against cognitive decline and suggests the need for future research to investigate how physical activity may interact with genetics and decrease Alzheimer’s risk."
Dr. Smith has previously shown that a walking exercise intervention for patients with mild cognitive decline improved cognitive function by improving the efficiency of brain activity associated with memory. He is planning to conduct a prescribed exercise intervention in a population of healthy older adults with genetic and other risk factors for Alzheimer’s disease and to measure the impact on hippocampal volume and brain function.
(Source: umdrightnow.umd.edu)
Loss of Memory in Alzheimer’s Mice Models Reversed through Gene Therapy
Alzheimer’s disease is the first cause of dementia and affects some 400,000 people in Spain alone. However, no effective cure has yet been found. One of the reasons for this is the lack of knowledge on the cellular mechanisms which cause alterations in nerve transmissions and the loss of memory in the initial stages of the disease.
Researchers from the Institute of Neuroscience at the Universitat Autònoma de Barcelona have discovered the cellular mechanism involved in memory consolidation and were able to develop a gene therapy which reverses the loss of memory in mice models with initial stages of Alzheimer’s disease. The therapy consists in injecting into the hippocampus - a region of the brain essential to memory processing - a gene which causes the production of a protein blocked in patients with Alzheimer’s, the “Crtc1” (CREB regulated transcription coactivator-1). The protein restored through gene therapy gives way to the signals needed to activate the genes involved in long-term memory consolidation.
To identify this protein, researchers compared gene expression in the hippocampus of healthy control mice with that of transgenic mice which had developed the disease. Through DNA microchips, they identified the genes (“transcriptome”) and the proteins (“proteome”) which expressed themselves in each of the mice in different phases of the disease. Researchers observed that the set of genes involved in memory consolidation coincided with the genes regulating Crtc1, a protein which also controls genes related to the metabolism of glucose and to cancer. The alteration of this group of genes could cause memory loss in the initial stages of Alzheimer’s disease.
In persons with the disease, the formation of amyloid plaque aggregates, a process known to cause the onset of Alzheimer’s disease, prevents the Crtc1 protein from functioning correctly. “When the Crtc1 protein is altered, the genes responsible for the synapsis or connections between neurons in the hippocampus cannot be activated and the individual cannot perform memory tasks correctly”, explains Carlos Saura, researcher of the UAB Institute of Neuroscience and head of the research. According to Saura, “this study opens up new perspectives on therapeutic prevention and treatment of Alzheimer’s disease, given that we have demonstrated that a gene therapy which activates the Crtc1 protein is effective in preventing the loss of memory in lab mice”.
The research, published today as a featured article in The Journal of Neuroscience, the official journal of the US Society of Neuroscience, paves the way for a new therapeutic approach to the disease. One of the main challenges in finding a treatment for the disease in the future is the research and development of pharmacological therapies capable of activating the Crtc1 protein, with the aim of preventing, slowing down or reverting cognitive alterations in patients.
Toward unraveling the Alzheimer’s mystery
Getting to the bottom of Alzheimer’s disease has been a rapidly evolving pursuit with many twists, turns and controversies. In the latest crook in the research road, scientists have found a new insight into the interaction between proteins associated with the disease. The report, which appears in the journal ACS Chemical Neuroscience, could have important implications for developing novel treatments.
Witold K. Surewicz, Krzysztof Nieznanski and colleagues explain that for years, research has suggested a link between protein clumps, known as amyloid-beta plaques, in the brain and the development of Alzheimer’s, a devastating condition expected to affect more than 10 million Americans by 2050. But how they inflict their characteristic damage to nerve cells and memory is not fully understood. Recent studies have found that a so-called prion protein binds strongly to small aggregates of amyloid-beta peptides. But the details of how this attachment might contribute to disease — and approaches to treat it — are still up for debate. To resolve at least part of this controversy, Surewicz’s team decided to take a closer look.
Contrary to previous studies, they found that the prion protein also attaches to large fibrillar clumps of amyloid-beta and do not break them down into smaller, more harmful pieces, as once thought. This finding bodes well for researchers investigating a novel approach to treating Alzheimer’s — using prion-protein-based compounds to stop these smaller, toxic amyloid-beta pieces from forming, the authors conclude.
(Image caption: Researchers have identified a new class of compounds—pharmacologic chaperones—that can stabilize the retromer protein complex (the blue and orange structure shows part of the complex). Retromer plays a vital role in keeping amyloid precursor from being cleaved and producing the toxic byproduct amyloid beta, which contributes to the development of Alzheimer’s. The study found that when the chaperone named R55 (the multicolored molecule) was added to neurons in cell culture, it bound to and stabilized retromer, increasing retromer levels and lowering amyloid-beta levels. Credit: Nature Chemical Biology and lab of Scott A. Small, MD/Columbia University Medical Center.)
“Chaperone” Compounds Offer New Approach to Alzheimer’s Treatment
A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer’s disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer’s.
Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.
“Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,” said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer’s Disease Research Center in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at CUMC, and a senior author of the paper. “This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins.”
In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer’s disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer’s-like symptoms. Retromer abnormalities have also been observed in Parkinson’s disease.
In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. “The idea that it would be beneficial to protect a protein’s structure is one that nature figured out a long time ago,” said Dr. Petsko. “We’re just learning how to do that pharmacologically.”
Other researchers had already determined retromer’s three-dimensional structure. “Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer’s weak point and stabilize the whole protein complex,” said Dr. Ringe.
This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.
The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. “One concern was that this compound would be toxic,” said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. “But R55 was found to be relatively non-toxic in mouse neurons in cell culture.”
More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer’s. The researchers are currently testing the clinical effects of R55 in the actual mouse model .
“The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,” said Dr. Petsko. “While we’re testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”
Researchers discover novel function of protein linked to Alzheimer’s disease
A research team led by the National Neuroscience Institute (NNI) has uncovered a novel function of the Amyloid Precursor Protein (APP), one of the main pathogenic culprits of Alzheimer’s disease. This discovery may help researchers understand how the protein goes awry in the brains of Alzheimer’s disease patients, and potentially paves the way for the development of innovative therapeutics to improve the brain function of dementia patients.
The findings were published in the prestigious scientific research journal Nature Communications last month. The study, which is led by Dr Zeng Li and her team from NNI, involved investigators from Duke-NUS Graduate Medical School and the Agency for Science and Technology (A*STAR).
Alzheimer’s disease is the most common form of dementia, which is set to rise significantly from the current 28,000 cases to 80,000 cases in 2030 among Singaporeans aged 60 and above. With a rapidly aging population, the burden of the disease will be profound affecting not just the person afflicted, but also the caregiver and family. While the exact cause of Alzheimer’s disease remains unknown, one of its pathological hallmarks is clear – the clumping of APP product in the brain when the protein is abnormally processed.
Finding out more about APP can help researchers gain a better understanding of the disease, and potentially identify biomarkers and therapeutic targets for it. However up till this point, little was known about the APP’s primary function in the brain.
(Source: eurekalert.org)
Alzheimer’s and Cancer Link Found
A team led by Houston Methodist Research Institute (HMRI) scientists has found that Alzheimer’s disease and cancer share a pathway in gene transcription, a process essential for cell reproduction and growth. They published their findings in December 2013 in the open access journal Scientific Reports by the Nature Publishing Group.
The scientists used the Lonestar and Stampede supercomputers at the Texas Advanced Computing Center (TACC) at The University of Texas at Austin to analyze and compare data from thousands of genes and to narrow the search for common cell signaling pathways of the two diseases. The Lonestar and Stampede systems are part of the Extreme Science and Engineering Discovery Environment (XSEDE), a single virtual system that scientists use to interactively share computing resources, data and expertise. The research is supported by a gift from the T.T. and W.F. Chao Foundation, and by grants from the National Institutes of Health (NIH).
Lead investigator Stephen Wong, a medical researcher and bioengineer with HMRI, said his study showed a new link between Alzheimer’s disease, the most prevalent form of neurodegenerative disease, and glioblastoma multiform (GBM), the most aggressive form of brain cancer.
"This is the first time people have found that at the molecular mechanism level there are linkages between the two diseases," Wong said.
A 2012 study in Taiwan and a 2013 study in Italy of public health data had shown an inverse association between Alzheimer’s disease, a severe degeneration of the brain’s nerve cells, and with cancer, where cells grow out of control.
"No one understands why this link is there, in a biological sense," Wong said. "And that’s the reason we did this study. I think we are among the first to study it this way."