Posts tagged alzheimer
Posts tagged alzheimer
Pathological changes typical of Alzheimer’s disease were significantly reduced in mice by blockade of an immune system transmitter. A research team from Charité - Universitätsmedizin Berlin and the University of Zurich has just published a new therapeutic approach in fighting Alzheimer’s disease in the current issue of Nature Medicine. This approach promises potential in prevention, as well as in cases where the disease has already set in.
The accumulation of particular abnormal proteins, including amyloid-ß (Aβ) among others, in patients’ brains plays a central role in this disease. Prof. Frank Heppner from the Department of Neuropathology at Charité and his colleague Prof. Burkhard Becher from the Institute for Experimental Immunology at the University of Zurich were able to show that turning off particular cytokines (immune system signal transmitters) reduced the Alzheimer’s typical amyloid-ß deposits in mice with the disease. As a result, the strongest effects were demonstrated after reducing amyloid-ß by approximately 65 percent, when the immune molecule p40 was affected, which is a component of the cytokines interleukin (IL)-12 and -23.
The discovery of the molecular pathway that drives the changes seen in the brains of Alzheimer’s patients is reported today, revealing new targets for drug discovery that could be exploited to combat the disease. The study gives the most detailed understanding yet of the complex processes leading to Alzheimer’s.
Alzheimer’s disease is associated with plaques made up of deposits of a molecule called amyloid between brain cells, which leads to the formation of tangles of twisted fibres made from a molecule called tau, found inside the brain cells. This causes the death of brain cells which is thought to bring about the symptoms of memory loss and dementia. Although it has been accepted for over twenty years that the progression of disease is driven by amyloid and results in abnormal changes in tau, the exact mechanisms of disease remain somewhat of a mystery.
Recent genome wide association studies have identified the gene for a molecule called clusterin as a susceptibility factor for late-onset Alzheimer’s disease. Levels of clusterin are also known to be elevated in blood in patients with Alzheimer’s from an early stage in the disease so the researchers wanted to find out what role it might play in the progression of disease.
The team, led by researchers at King’s College London’s Institute of Psychiatry, looked first in mouse brain cells grown in the laboratory and found that the presence of amyloid alters the amount of clusterin in these cells. Clusterin then acts to switch on a signalling pathway that drives the changes in tau that are associated with the formation of tangles inside the cells, another hallmark of the disease. When this signalling pathway was chronically switched on in a mouse model of the disease, the researchers observed an increase in tangle formation and evidence of cognitive defects.
The study, published in the journal Molecular Psychiatry, also looked in humans and detected the signature of clusterin activation in the brains of Alzheimer’s patients but not in the brains of patients with other forms of dementia.
Dr Richard Killick from King’s College London’s Institute of Psychiatry said: “This is the first time we’ve been able to connect the molecular mechanisms behind the formation of amyloid plaques in the brain with the formation of tangles inside the brain cells, two of the defining features of Alzheimer’s disease. Our research has given the most detailed picture yet of how the disease progresses and we hope it will offer leads for the development of new treatments.”
The signalling pathway that is turned on by clusterin is called DKK1-WNT. It involves interactions between a number of different molecules that could prove to be useful targets for the development of new drugs.
Current treatments for Alzheimer’s are focused on alleviating the symptoms and there is no therapy that can prevent the progression of disease.
Professor Simon Lovestone, also from King’s College London’s Institute of Psychiatry, who led the study, said: “We have shown that we can block the toxic effects of amyloid when we stop this signalling pathway in brain cells grown in the lab. We believe that if we could block its activity in the brains of Alzheimer’s patients too, we may have an opportunity to halt the disease in man. Indeed, we have already begun our own drug development programme to do just that and are at the stage where potential compounds are coming back to us for further testing.”
The DKK1-WNT pathways has also been implicated in some human cancers and although there is no evidence for a direct link, the findings from this study mean that there could be an opportunity to make advances in Alzheimer’s research by capitalising on knowledge that is being gained from cancer research, the authors suggest.
Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, which helped fund this study, said: “We will see more and more people affected by Alzheimer’s disease as our population ages. This study gives us a much-needed additional insight to the complex biology that contributes to the development of Alzheimer’s, which is vital if we are to develop new treatments that are so urgently needed.”
A gene that confers a higher risk for dementia in old age could also promote better-than-average memory and verbal skills in youth, according to a new University of Sussex-led study.
Neuroscientists tested the cognitive abilities of those with a particular gene variant, known as ‘APOE e4’, found in approximately 25 per cent of the population, against those without it. They also looked at the brain structure and brain activities of both groups during the tasks.
They found that young people with the e4 variant performed better in attention tests (one involving episodic memory of words, the other requiring participants to spot number sequences), which correlated with increased task-related brain activation as detected by MRI scans. The researchers also noticed subtle differences in the white matter of the brains of those with the variant.
Lead researcher Professor Jennifer Rusted said: “Earlier studies suggested that those with the e4 variant outperform those without it in tasks such as memory, speed of processing, mental arithmetic and verbal fluency.
But it is also well-established that this gene is a risk factor for Alzheimer’s disease. The suggestion is that while this confers cognitive advantages in early life, leading to higher achievement, it may also increase susceptibility to memory failure as we enter old age.
“Our study is the first to show that subtle differences in the structure and activation of the brain during cognitive tasks in APOE e4 carriers are linked to their cognitive performance. It is possible that the brain over-activations that we see in youth have negative effects over the longer term and contribute to a kind of ‘burnout’ in older adulthood.”
‘APOE e4 polymorphism in young adults is associated with improved attention andindexed by distinct neural signatures’, by Professor Jennifer Rusted, Dr Simon Evans and Dr Sarah King in the School of Psychology, Dr Nick Dowell and Professor Paul Tofts in the Clinical Imaging Sciences Centre at the Brighton and Sussex Medical School (BSMS), and Dr Najo Tabet in the BSMS Institute of Postgraduate Medicine, is published in NeuroImage.
New, Improved Mouse Model of Human Alzheimer’s May Enable Drug Discovery
Researchers at the University of Illinois at Chicago College of Medicine have developed a transgenic mouse that carries a human gene known to increase risk of Alzheimer’s 15-fold. This new mouse mimics the genetics of the human disease more closely than any of the dozen existing mouse models and may prove more useful in the development of candidate drugs to prevent or treat the disease.
The new mouse model provides new evidence for the earliest cause of Alzheimer’s, researchers report in a study to be published in the December issue of the Journal of Biological Chemistry and now available online.
The model is a cross between an existing transgenic Alzheimer’s mouse and a mouse carrying fully human apoE, a gene that in one of its three variants, apoE4, is the greatest genetic risk factor for Alzheimer’s in the human population.
UC Irvine researchers have created a new stem cell-derived cell type with unique promise for treating neurodegenerative diseases such as Alzheimer’s.
Dr. Edwin Monuki of UCI’s Sue & Bill Gross Stem Cell Research Center, developmental & cell biology graduate student Momoko Watanabe and colleagues developed these cells — called choroid plexus epithelial cells — from existing mouse and human embryonic stem cell lines.
CPECs are critical for proper functioning of the choroid plexus, the tissue in the brain that produces cerebrospinal fluid. Among their various roles, CPECs make CSF and remove metabolic waste and foreign substances from the fluid and brain.
In neurodegenerative diseases, the choroid plexus and CPECs age prematurely, resulting in reduced CSF formation and decreased ability to flush out such debris as the plaque-forming proteins that are a hallmark of Alzheimer’s. Transplant studies have provided proof of concept for CPEC-based therapies. However, such therapies have been hindered by the inability to expand or generate CPECs in culture.
“Our method is promising, because for the first time we can use stem cells to create large amounts of these epithelial cells, which could be utilized in different ways to treat neurodegenerative diseases,” said Monuki, an associate professor of pathology & laboratory medicine and developmental & cell biology at UCI.
The study appears in The Journal of Neuroscience
To create the new cells, Monuki and his colleagues coaxed embryonic stem cells to differentiate into immature neural stem cells. They then developed the immature cells into CPECs capable of being delivered to a patient’s choroid plexus.
These cells could be part of neurodegenerative disease treatments in at least three ways, Monuki said. First, they’re able to increase the production of CSF to help flush out plaque-causing proteins from brain tissue and limit disease progression. Second, CPEC “superpumps” could be designed to transport high levels of therapeutic compounds to the CSF, brain and spinal cord. Third, these cells can be used to screen and optimize drugs that improve choroid plexus function.
Monuki said the next steps are to develop an effective drug screening system and to conduct proof-of-concept studies to see how these CPECs affect the brain in mouse models of Huntington’s, Alzheimer’s and pediatric diseases.
When it comes to Alzheimer’s disease, scientists usually — and understandably — look to the brain as their first center of attention. Now researchers at Tel Aviv University say that early clues regarding the progression of the disease can be found in the brain’s metabolism.
In very early stages of the disease, before any symptoms appear, metabolic processes are already beginning to change in the brain, says PhD candidate Shiri Stempler of TAU’s Sackler Faculty of Medicine. Working with Profs. Eytan Ruppin and Lior Wolf of TAU’s Blavatnik School of Computer Science, Stempler has developed predictor models that use metabolic information to pinpoint the progression of Alzheimer’s. These models were 90 percent accurate in predicting the stage of the disease.
Published in the journal Neurobiology of Aging, the research is the first step towards identifying biomarkers that may ensure better detection and analysis of the disease at an early stage, all with a simple blood test. It could also lead to novel therapies. “We hope that by studying metabolism, and the alterations to metabolism that occur in the very early stages of the disease, we can find new therapeutic strategies,” adds Stempler.
Over the last 15 years, researchers have found a significant association between vascular diseases such as hypertension, atherosclerosis, diabetes type 2, hyperlipidemia, and heart disease and an increased risk of Alzheimer’s disease. In a special issue of the Journal of Alzheimer’s Disease, leading experts provide a comprehensive overview of the pathological, biochemical, and physiological processes that contribute to Alzheimer’s disease risk and ways that may delay or reverse these age-related abnormalities.
“Vascular risk factors to Alzheimer’s disease offer the possibility of markedly reducing incident dementia by early identification and appropriate medical management of these likely precursors of cognitive deterioration and dementia,” says Guest Editor Jack C. de la Torre, MD, PhD, of the University of Texas, Austin. “Improved understanding coupled with preventive strategies could be a monumental step forward in reducing worldwide prevalence of Alzheimer’s disease, which is doubling every 20 years.”
The issue explores how vascular disease can affect cerebral blood flow and impair signaling, contributing to Alzheimer’s disease (AD). The diagnostics of cardiovascular risk factors in AD are addressed, as are potential therapeutic approaches.
Paradoxically, the presence of vascular risk factors in middle age is associated with the development of AD more strongly than late-life vascular disease. In fact, some research suggests that vascular symptoms later in life may have a protective effect against the development of the disease. The physiopathological mechanisms that may underlie this phenomenon are discussed.
To date, trials that target major cardiovascular risk factors in the prevention of AD remain inconclusive but have become an important focus of international research as described by contributors of this special volume in their overviews. The multifactorial nature of AD and the need to identify the proper time window for intervention when designing possible interventions, and methodological issues that will have to be addressed to achieve an optimal design of new randomized controlled trials, are discussed. Promising avenues for treatment, such as the potential of low-level light therapy to increase the rate of oxygen consumption in the brain and enhance cortical metabolic capacity, and the possibility that some antihypertensive drug classes reduce the risk and progression of AD more than others, are discussed.
Dr. de la Torre notes that the presence of vascular risk factors is not an absolute pathway to dementia, and it may be as important to study how or why individuals who are cognitively normal but have vascular risk are able to avoid dementia. “Reducing Alzheimer’s disease prevalence by focusing right now on vascular risk factors to Alzheimer’s disease, even with our limited technology, is not a simple or easy task. But the task must begin somewhere and without delay because time is running out for millions of people whose destiny with dementia may start sooner rather than later,” he concludes.
Using solid-state nuclear magnetic resonance (NMR) spectroscopy, researchers at Luleå University of Technology in collaboration with Warwick University in the UK for the first time in the world managed to analyse hydrogen bonds in tiny fibrils of Amyloid-beta peptide, which probably causes Alzheimer’s disease. Thanks to these new results, there is a successful method avaliable – for analysis of structure of Amyloid-beta peptides in their most toxic form, that is, when they are most dangerous for the brain neurons.
- This is a very important step in research on Alzheimer’s disease at a molecular level, says Oleg N. Antzutkin, professor in chemistry of interfaces, at Luleå University of Technology.
Until a few years ago scientists believed that amyloid plaques in the brain directly cause Alzheimer’s disease. This is because very large amounts of plaques in the brain of Alzheimer´s patients are usually found. Since the activity of our brain is greatest in the regions responsible for short-term memory, there most of the amyloid plaques were found. Here is also usually where Alzheimer’s disease is first noticed, in the form of reduced short-term memory. However, it seems to be that Amyloid plaque are rather a residual of something worse.
Bacteria yield clues about why proteins go bad in ALS and Alzheimer’s
Scientists are unsure why proteins form improperly and cluster together in bunches, a hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s and Mad Cow Disease. In the Nov. 1 issue of the journal Molecular Cell, Yale scientists shed light on protein aggregate formation by studying the process in bacteria.
“The question we are all asking is what happens when protein synthesis goes wrong?” said Jesse Rinehart, assistant professor of cellular and molecular physiology at Yale’s West Campus and co-senior author of the paper.
Proteins are created from instructions encoded in DNA and assembled in ribosomes within the cells. However, sometimes they are not assembled correctly, and these misfolded proteins tend to aggregate, a process typified by the plaques that form in the brains of Alzheimer’s patients.
The Yale team — led by Rinehart and Dieter Söll, Sterling Professor of Molecular Biophysics and Biochemistry and professor of chemistry — showed that the antibiotic streptomycin can trigger protein aggregations in the bacterium E. coli. Using large-scale proteomics and genetic screens, they analyzed the aggregates and searched for bacterial proteins that make E. coli cells resistant to antibiotics and other threats. The researchers discovered how one of these proteins protecting the bacteria from hydrogen peroxide also suppressed the aggregation of proteins triggered by streptomycin.
Research led by Chu Chen, PhD, Associate Professor of Neuroscience at LSU Health Sciences Center New Orleans, has identified an enzyme called Monoacylglycerol lipase (MAGL) as a new therapeutic target to treat or prevent Alzheimer’s disease. The study was published online November 1, 2012 in the Online Now section of the journal Cell Reports.
The research team found that inactivation of MAGL, best known for its role in degrading a cannabinoid produced in the brain, reduced the production and accumulation of beta amyloid plaques, a pathological hallmark of Alzheimer’s disease. Inhibition of this enzyme also decreased neuroinflammation and neurodegeneration, and improved plasticity of the brain, learning and memory.
"Our results suggest that MAGL contributes to the cause and development of Alzheimer’s disease and that blocking MAGL represents a promising therapeutic target," notes Dr. Chu Chen, who is also a member of the Department of Otolaryngology at LSU Health Sciences Center New Orleans.
The researchers blocked MAGL with a highly selective and potent inhibitor in mice using different dosing regimens and found that inactivation of MAGL for eight weeks was sufficient to decrease production and deposition of beta amyloid plaques and the function of a gene involved in making beta amyloid toxic to brain cells. They also measured indicators of neuroinflammation and neurodegeneration and found them suppressed when MAGL was inhibited. The team discovered that not only did the integrity of the structure and function of synapses associated with cognition remain intact in treated mice, but MAGL inactivation appeared to promote spatial learning and memory, measured with behavioral testing.
Alzheimer’s disease is a neurodegenerative disorder characterized by accumulation and deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, synaptic dysfunction, progressive deterioration of cognitive function and loss of memory in association with widespread nerve cell death. The most common cause of dementia among older people, more than 5.4 million people in the United States and 36 million people worldwide suffer with Alzheimer’s disease in its various stages. Unfortunately, the few drugs that are currently approved by the Food and Drug Administration have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods, and none has shown a clear effect on disease progression or prevention.
"There is a great public health need to discover new therapies to prevent and treat this devastating disorder," Dr. Chen concludes. The research was supported by grants from the National Institutes of Health. In addition to scientists from LSU Health Sciences Center New Orleans, the research team also included investigators from the Massachusetts Institute of Technology.