Posts tagged alzheimer's disease
Articles and news from the latest research reports.
Study finds modified stem cells offer potential pathway to treat Alzheimer’s disease
UC Irvine neurobiologists have found that genetically modified neural stem cells show positive results when transplanted into the brains of mice with the symptoms and pathology of Alzheimer’s disease. The pre-clinical trial is published in the journal Stem Cells Research and Therapy, and the approach has been shown to work in two different mouse models.
Alzheimer’s disease, one of the most common forms of dementia, is associated with accumulation of the protein amyloid-beta in the brain in the form of plaques. While the search continues for a viable treatment, scientists are now looking into non-pharmaceutical ways to slow onset of this disease.
One option being considered is increasing the production of the enzyme neprilysin, which breaks down amyloid-beta, and shows lower activity in the brains of people with Alzheimer’s disease. Researchers from UC Irvine investigated the potential of decreasing amyloid-beta by delivering neprilysin to mice brains.
“Studies suggest that neprilysin decreases with age and may therefore influence the risk of Alzheimer’s disease,” said Mathew Blurton-Jones, an assistant professor of neurobiology & behavior. “If amyloid accumulation is the driving cause of Alzheimer’s disease, then therapies that either decrease amyloid-beta production or increase its degradation could be beneficial, especially if they are started early enough.”
The brain is protected by a system called the blood-brain-barrier that restricts access of cells, proteins, and drugs to the brain. While the blood-brain-barrier is important for brain health, it also makes it challenging to deliver therapeutic proteins or drugs to the brain. To overcome this, the researchers hypothesized that stem cells could act as an effective delivery vehicle. To test this hypothesis the brains of two different mouse models (3xTg-AD and Thy1-APP) were injected with genetically modified neural stem cells that over-expressed neprilysin.
These genetically modified stem cells were found to produce 25-times more neprilysin than control neural stem cells, but were otherwise equivalent to the control cells. The genetically modified and control stem cells were then transplanted into the hippocampus or subiculum of the mice brains – two areas of the brain that are greatly affected by Alzheimer’s disease. The mice transplanted with genetically modified stem cells were found to have a significant reduction in amyloid-beta plaques within their brains compared to the controls. The effect remained even one month after stem cell transplantation. This new approach could provide a significant advantage over unmodified neural stem cells because neprilysin-expressing cells could not only promote the growth of brain connections but could also target and reduce amyloid-beta pathology.
Before this can be investigated in humans, more work needs to be done to see if this affects the accumulation of soluble forms of amyloid-beta. Further investigation is also needed to determine whether this new approach improves cognition more than the transplantation of un-modified neural stem cells.
“Every mouse model of Alzheimer’s disease is different and develops varying amounts, distribution, and types of amyloid-beta pathology,” Blurton-Jones said. “By studying the same question in two independent transgenic models, we can increase our confidence that these results are meaningful and applicable to Alzheimer’s disease. But there is clearly a great deal more research needed to determine whether this kind of approach could eventually be translated to the clinic.”
Gene variant puts women at higher risk of Alzheimer’s than it does men
Carrying a copy of a gene variant called ApoE4 confers a substantially greater risk for Alzheimer’s disease on women than it does on men, according to a new study by researchers at the Stanford University School of Medicine.
The scientists arrived at their findings by analyzing data on large numbers of older individuals who were tracked over time and noting whether they had progressed from good health to mild cognitive impairment — from which most move on to develop Alzheimer’s disease within a few years — or to Alzheimer’s disease itself.
The discovery holds implications for genetic counselors, clinicians and individual patients, as well as for clinical-trial designers. It could also help shed light on the underlying causes of Alzheimer’s disease, a progressive neurological syndrome that robs its victims of their memory and ability to reason. Its incidence increases exponentially after age 65. An estimated one in every eight people past that age in the United States has Alzheimer’s. Experts project that by mid-century, the number of Americans with Alzheimer’s will more than double from the current estimate of 5-6 million.
According to the Alzheimer’s Association, it is already the nation’s most expensive disease, costing more than $200 million annually. (The epidemiology of mild cognitive impairment is fuzzier, but this gateway syndrome is clearly more widespread than Alzheimer’s.)
(Image caption: Blockade of p25 generation in the brain of an Alzheimer’s disease mouse model mitigates amyloid plaque buildup. Hippocampal slices from a seven-month-old 5XFAD mouse (left) or 5XFAD;p35KI mouse (right), alongside markers for Aβ (red) and activated astrocyte (green). Nuclei are shown in blue.)
Limiting a certain protein in the brain reverses Alzheimer’s symptoms in mice, report neuroscientists at MIT’s Picower Intitute for Learning and Memory.
Researchers found that the overproduction of the protein known as p25 may be the culprit behind the sticky protein-fragment clusters that build up in the brains of Alzheimer’s patients. The work, which was published in the April 10 issue of Cell, could provide a new drug target for the treatment of the disease that affects more than five million Americans, says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and senior author of the paper.
Abnormal clusters of protein fragments, known as beta amyloid plaques, are believed to cause the cognitive impairments, cell death, and tissue loss associated with Alzheimer’s. The p25 protein had been tied to the creation and buildup of beta amyloids, but until now, p25’s role in Alzheimer’s pathology was not well understood.
“This protein appears to help maintain normal brain activity, but also is part of a feedback loop with beta amyloids. It generates the plaques which, in turn, boost levels of p25,” Tsai says.
Lead author of the paper is Jinsoo Seo, a postdoc associate at the Picower Institute.
The benefits of p25 generation
Elevated p25 levels in the brain have been documented upon exposure to neurotoxic stimuli such as oxidative stress and beta amyloids.
“In this study, for the first time we show that a variety of physiological neuronal activities generate p25 in the hippocampus, where memories are encoded in the brain,” Tsai says.
To delineate the precise roles of p25, Tsai’s lab generated a transgenic mouse model, which enabled researchers to prevent the production of p25 without altering other proteins with essential roles in brain development.
The researchers found that p25 is required for synaptic plasticity, the ability of brain connections to change over time; especially for the process called long-term depression (LTD) that selectively weakens sets of synapses and is associated with memory extinction.
Tsai’s team observed that the mice unable to generate p25 could learn new tasks and form memories normally; however, when the researchers began to address memory extinction, they soon noticed that the mice have difficulties with replacing older memories with newer ones.
Too much of a good thing
“This finding not only boosts our understanding of p25 in synaptic functions, but also explains the underlying mechanism of the inordinate synaptic depression observed in the Alzheimer’s brain,” Seo says.
“This finding led us to question whether the blockade of p25 generation could mitigate pathological phenotypes in the Alzheimer’s brain,” Tsai says.
In the mouse model of Alzheimer’s disease, inhibiting p25 production improved cognitive function, greatly reduced plaque formation and neuroinflammation, hallmark features of Alzheimer’s disease.
These results hold out the hope that a drug that regulates p25 could benefit Alzheimer’s disease patients by improving cognitive function and perhaps delaying the development of brain pathology, Tsai says.
New mouse model could revolutionize research in Alzheimer’s disease
In a study published today in Nature Neuroscience, a group of researchers led by Takaomi Saido of the RIKEN Brain Science Institute in Japan have reported the creation of two new mouse models of Alzheimer’s disease that may potentially revolutionize research into this disease.
Alzheimer’s disease, the primary cause of dementia in the elderly, imposes a tremendous social and economic burden on modern society. In Japan, the burden of the disease in 2050 is estimated to be a half a trillion US dollars, a figure equivalent to the government’s annual revenues.
Unfortunately, it has proven very difficult to develop drugs capable of ameliorating the disease. After a tremendous burst of progress in the 1990s, the pace of discoveries has slowed. Dr. Saido believes that part of the difficulty is the inadequacy of current mouse models to replicate the real conditions of Alzheimer’s disease and allow an understanding of the underlying mechanisms that lead to neurodegeneration. In fact, much of the research in Alzheimer’s disease over the past decade may be flawed, as it was based on unrealistic models.
The problem with older mouse models is that they overexpress a protein called amyloid precursor protein, or APP, which gives rise to the amyloid-beta (Abeta) peptides that accumulate in the brain, eventually leading to the neurodegeneration that characterizes Alzheimer’s disease. However, in mice the overexpression of APP gives rise to effects which are not seen in human Alzheimer’s disease.
For example, the APP mutant mice often die of unknown causes at a young age, and the group believes this may be related to the generation of toxic fragments of APP, such as CTF-beta. In addition, some of the fragments of APP could be neuroprotective, making it difficult to judge whether drugs are being effective due to their effect on Abeta peptides, which are known to be involved in human AD, or whether it is due to other effects that would not be seen in human disease. In addition, the gene for expressing APP is inserted in different places in the genome, and may knock out other genes, creating artifacts that are not seen in humans.
With this awareness, more than a decade ago Dr. Saido launched a project to develop a new mouse model that would allow more accurate evaluation of therapies for the disease. One of the major hurdles involved a part of the gene, intron 16, which they discovered was necessary for creating more specific models.
The first mice model they developed (NL-F/NL-F) was knocked in with two mutations found in human familial Alzheimer’s disease. The mice showed early accumulation of Abeta peptides, and importantly, were found to undergo cognitive dysfunction similar to the progression of AD seen in human patients. A second model, with the addition of a further mutation that had been discovered in a family in Sweden, showed even faster initiation of memory loss.
These new models could help in two major areas. The first model, which expresses high levels of the Abeta peptides, seems to realistically model the human form of AD, and could be used for elucidating the mechanism of Abeta deposition. The second model, which demonstrates AD pathology very early on, could be used to examine factors downstream of Abeta-40 and Abeta-42 deposition, such as tauopathy, which are believed to be involved in the neurodegeneration. These results may eventually contribute to drug development and to the discovery of new biomarkers for Alzheimer’s disease. The group is currently looking at several proteins, using the new models, which have potential to be biomarkers.
According to Dr. Saido, “We have a social responsibility to make Alzheimer’s disease preventable and curable. The generation of appropriate mouse models will be a major breakthrough for understanding the mechanism of the disease, which will lead to the establishment of presymptomatic diagnosis, prevention and treatment of the disease.”
Caffeine against Alzheimer’s disease
A team of researchers working with Prof. Dr. Christa E. Müller from the University of Bonn demonstrates a positive effect on tau deposits
As part of a German-French research project, a team led by Dr. Christa E. Müller from the University of Bonn and Dr. David Blum from the University of Lille was able to demonstrate for the first time that caffeine has a positive effect on tau deposits in Alzheimer’s disease. The two-years project was supported with 30,000 Euro from the non-profit Alzheimer Forschung Initiative e.V. (AFI) and with 50,000 Euro from the French Partner organization LECMA. The initial results were published in the online edition of the journal “Neurobiology of Aging”
Tau deposits, along with beta-amyloid plaques, are among the characteristic features of Alzheimer’s disease. These protein deposits disrupt the communication of the nerve cells in the brain and contribute to their degeneration. Despite intensive research there is no drug available to date which can prevent this detrimental process. Based on the results of Prof. Dr. Christa Müller from the University of Bonn, Dr. David Blum and their team, a new class of drugs may now be developed for the treatment of Alzheimer’s disease.
Caffeine, an adenosine receptor antagonist, blocks various receptors in the brain which are activated by adenosine. Initial results of the team of researchers had already indicated that the blockade of the adenosine receptor subtype A2A in particular could play an important role. Initially, Prof. Müller and her colleagues developed an A2A antagonist in ultrapure and water-soluble form (designated MSX-3). This compound had fewer adverse effects than caffeine since it only blocks only the A2A adenosine receptor subtype, and at the same time it is significantly more effective. Over several weeks, the researchers then treated genetically altered mice with the A2A antagonist. The mice had an altered tau protein which, without therapy, leads to the early development of Alzheimer’s symptoms.
In comparison to a control group which only received a placebo, the treated animals achieved significantly better results on memory tests. The A2A antagonist displayed positive effects in particular on spatial memory. Also, an amelioration of the pathogenic processes was demonstrated in the hippocampus, which is the site of memory in rodents.
"We have taken a good step forward," says Prof. Müller. "The results of the study are truly promising, since we were able to show for the first time that A2A adenosine receptor antagonists actually have very positive effects in an animal model simulating hallmark characteristics and progression of the disease. And the adverse effects are minor."
The researchers now want to test the A2A antagonist in additional animal models. If the results are positive, a clinical study may follow. “Patience is required until A2A adenosine receptor antagonists are approved as new therapeutic agents for Alzheimer’s disease. But I am optimistic that clinical studies will be performed,” says Prof. Müller.
(Image: Shutterstock)
‘Sewing machine’ idea gives insight into origins of Alzheimer’s
Researchers at Lancaster University have invented a new imaging tool inspired by the humble sewing machine which is providing fresh insight into the origins of Alzheimer’s and Parkinson’s disease.
These diseases are caused by tiny toxic proteins too small to be studied with traditional optical microscopy.
Previously it was thought that Alzheimer’s was caused by the accumulation of long ‘amyloid’ fibres at the centre of senile plaques in the brain, due to improper folding of a protein called amyloid-β.
But new research suggests that these fibres and plaques are actually the body’s protective response to the presence of even smaller, more toxic structures made from amyloid-β called ‘oligomers’.
Existing techniques are not sufficient to get a good look at these proteins; optical microscopy does not provide enough resolution at this scale, and electron microscopy gives the resolution but not the contrast.
To solve the problem, Physicist Dr Oleg Kolosov and his team at Lancaster have developed a new imaging technique - Ultrasonic Force Microscopy (UFM) - inspired by the motion of a sewing machine. Their work has been published in Scientific Reports.
Dr Kolosov said: “By using a vibrating scanner, which moves quickly up and down like the foot of a sewing machine needle, the friction between the sample and the scanner was reduced – resulting in a better quality, and high contrast nanometre scale resolution image.”
It is one of a new generation of tools being developed worldwide to bring the oligomers into focus, enabling medical researchers to understand how they behave.
At Lancaster, Claire Tinker used UFM to image these oligomers. To help see them more clearly she needed to increase the contrast of the image and used poly-L-lysine (PLL) which kept the proteins stuck to the slides as the vibrating scanner was passed over them.
Lancaster University Biomedical Scientist Professor David Allsop said: “These high quality images are vitally important if we are to understand the pathways involved in formation of these oligomers, and this new technique will now be used to test the effects of inhibitors of oligomer formation that we are developing as a possible new treatment for Alzheimer’s disease.”
The technique worked so well that the team now hopes to develop it so that oligomer formation can be monitored as they are made in real time.
This would give researchers a clearer understanding of the early phases of Alzheimer’s and Parkinson’s and could potentially be one way of developing a future test for these diseases.
(Source: alphagalileo.org)
High-fat diet in pregnancy linked to Alzheimer’s brain changes in offspring
A new study from scientists in Southampton has suggested that diet during pregnancy may affect an offspring’s risk of brain changes linked to Alzheimer’s disease. The research, which was funded by Alzheimer’s Research UK, studied adult mice whose mothers were fed either a normal or a high-fat diet during pregnancy and lactation. The study is due to be presented at Alzheimer’s Research UK Conference 2014 in Oxford this week.
Led by Dr Cheryl Hawkes at the University of Southampton, the team set out to investigate the links between obesity and Alzheimer’s. Obesity has been linked to a higher risk of the disease, and previous research has suggested that a mother’s diet during pregnancy may affect a child’s risk of obesity and conditions such as heart disease and diabetes in adulthood.
The researchers studied mice which were fed either a standard diet or a high-fat diet, and whose mothers were also fed either a high fat or standard diet during pregnancy and lactation. They then looked at markers of cholesterol and problems with blood vessels in the brain, both of which have been linked to Alzheimer’s.
They found that mice whose mothers ate a high-fat diet during pregnancy were more likely to have vascular changes in their brains later in life. Furthermore, when the offspring of mothers with a high-fat diet were also fed a high-fat diet, their brains’ blood vessels became less efficient at clearing the protein amyloid – a hallmark feature of the disease.
Dr Hawkes, an Alzheimer’s Research UK Senior Research Fellow at the University of Southampton, said: “Our preliminary findings suggest that mothers’ diets during pregnancy may have long-term effects on their children’s brains and vascular health. We still need to do more work to understand how our findings translate to humans, but we have known for some time that protecting mothers’ health during pregnancy can help lower the risk of health problems for their children. Our next step will be to investigate how our findings could relate to Alzheimer’s disease in people. We hope these results could provide a new lead for research to understand how to prevent the disease.”
Alzheimer’s Research UK is the UK’s leading dementia research charity, funding more than £20m of pioneering research into the condition across the UK. The charity’s annual conference on 25 and 26 March is the largest of its kind in the UK, and will see leading dementia scientists share their progress in the drive to defeat dementia.
Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said: “It’s important to remember that this research is in mice, but these results add to existing evidence suggesting that the risk of Alzheimer’s disease in later life is affected by our health earlier in life. This study goes one step further by suggesting that what happens in the womb may also be important. We’re pleased to have funded this research, which has shed new light on the complex picture of Alzheimer’s risk.
“Alzheimer’s is a complicated disease and it’s likely that our risk is affected by a number of different genetic and environmental factors. Research to understand these factors can help equip us to take steps to prevent the disease, but in the meantime, evidence suggests we can lower our risk by eating a healthy, balanced diet, doing regular exercise, not smoking and keeping our blood pressure and weight in check.”
How age opens the gates for Alzheimer’s
With advancing age, highly-evolved brain circuits become susceptible to molecular changes that can lead to neurofibrillary tangles — a hallmark of Alzheimer’s Disease, Yale researchers report the week of March 17 in the Proceedings of the National Academy of Sciences.
The findings not only help to explain why age is such a large risk factor for Alzheimer’s, but why the higher brain circuits regulating cognition are so vulnerable to degeneration while the sensory cortex remains unaffected.
“We hope that understanding the key molecular alterations that occur with advancing age can provide new strategies for disease prevention,” said Amy F.T. Arnsten, professor of neurobiology and one of the senior authors of the study.
Neurofibrillary tangles are made from a protein called tau, which becomes sticky and clumps together when modified in a process called phosphorylation. The Yale study found that phosphorylated tau collects in neurons in higher brain circuits of the aging primate brain, but does not accumulate in neurons of the sensory cortex. Phosphorylated tau collects in and near the excitatory connections called synapses where neurons communicate and can spread between cells in higher brain circuits, the study found.
The study led by Yale researchers Becky C. Carlyle, Angus Nairn, Arnsten and Constantinos D. Paspalas found clues about what causes tau to become phosphorylated with advancing age. They uncovered age-related changes in the molecular signals that control the strength of higher cortical connections. In young brains, an enzyme called phosphodiesterase PDE4A sits near the synapse where it inhibits a chemical “vicious cycle” that disconnects higher brain circuits when we are in danger, switching control of behavior to more primitive brain areas. They further found that PDE4A is lost in the aged prefrontal association cortex, unleashing a chemical cascade of events that increase the phosphorylation of tau. This process may be amplified in humans, where high order cortical neurons have even more excitatory connections, leading to tangle formation and ultimately cell death.
“This insight into one pathway by which tau may influence the onset and progression of Alzheimer’s disease takes us a step closer to unraveling this complex and devastating disorder,” said Dr. Molly Wagster, of the National Institutes of Health, a co-funder of the research.
The new study may also help to explain why head injury is a risk factor for Alzheimer’s, as it may also increase the activity of the chemical “vicious cycle.”
“Now that we begin to see what makes neurons vulnerable, we may be able to protect cells with treatments that mimic the protective effects of PDE4A,” said Arnsten.
Scientists slow development of Alzheimer’s trademark cell-killing plaques
University of Michigan researchers have learned how to fix a cellular structure called the Golgi that mysteriously becomes fragmented in all Alzheimer’s patients and appears to be a major cause of the disease.
They say that understanding this mechanism helps decode amyloid plaque formation in the brains of Alzheimer’s patients—plaques that kills cells and contributes to memory loss and other Alzheimer’s symptoms.
The researchers discovered the molecular process behind Golgi fragmentation, and also developed two techniques to ‘rescue’ the Golgi structure.
"We plan to use this as a strategy to delay the disease development," said Yanzhuang Wang, U-M associate professor of molecular, cellular and developmental biology. "We have a better understanding of why plaque forms fast in Alzheimer’s and found a way to slow down plaque formation."
The paper appears in an upcoming edition of the Proceedings of the National Academy of Sciences. Gunjan Joshi, a research fellow in Wang’s lab, is the lead author.
Wang said scientists have long recognized that the Golgi becomes fragmented in the neurons of Alzheimer’s patients, but until now they didn’t know how or why this fragmentation occurred.
The Golgi structure has the important role of sending molecules to the right places in order to make functional cells, Wang said. The Golgi is analogous to a post office of the cell, and when the Golgi becomes fragmented, it’s like a post office gone haywire, sending packages to the wrong places or not sending them at all.
U-M researchers found that the accumulation of the Abeta peptide—the primary culprit in forming plaques that kill cells in Alzheimer’s brains—triggers Golgi fragmentation by activating an enzyme called cdk5 that modifies Golgi structural proteins such as GRASP65.
Wang and colleagues rescued the Golgi structure in two ways: they either inhibited cdk5 or expressed a mutant of GRASP65 that cannot be modified by cdk5. Both rescue measures decreased the harmful Abeta secretion by about 80 percent.
The next step is to see if Golgi fragmentation can be delayed or reversed in mice, Wang said. This involves a collaboration with the Michigan Alzheimer’s Disease Center at the U-M Health System, directed by Dr. Henry Paulson, professor of neurology, and Geoffrey Murphy, assistant professor of physiology and research professor at the U-M Molecular and Behavioral Neuroscience Institute.