Posts tagged beta amyloid
Articles and news from the latest research reports.
Protein reelin rescues cognitive impairment in animal models of Alzheimer’s disease
The scientists Eduardo Soriano and Lluís Pujadas, from the University of Barcelona (UB), and the “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas” (CIBERNED) have led research into the role of reelin in animal models of Alzheimer’s disease.
Published today in the journal Nature Communications, the study demonstrates how an increase in the levels of reelin—a protein that is essential for cerebral cortex plasticity—has the capacity to restore cognitive capacity in mouse models of Alzheimer’s disease, delaying amyloid-beta (Αβ) fibril formation in vitro and reducing the accumulation of amyloid deposits in the brains of animals affected by this disease.
The study, which was started four years ago, has involved the collaboration of members of the Peptides and Proteins lab at the Institute for Research in Biomedicine (IRB), namely Bernat Serra-Vidal, PhD student, Ernest Giralt, group leader, and Natàlia Carulla, associate researcher whose investigation focuses on the aggregation of Αβ. Alzheimer’s disease, which affects approximately 500,000 people in Spain, is characterised by the loss of neural connections and by neuronal death, both associated mainly with the formation of senile plaques (extracellular deposits of Aβ) and the presence of neurofibrillary tangles (intracellular deposits of tau protein.
In the IRB lab, researchers have performed experiments in vitro to determine whether there is an interaction between Aβ aggregation and reelin. These assays have revealed that reelin interacts with the Aβ peptide, delaying the formation of Aβ fibrils until it is trapped within them. “When reelins becomes trapped in Aβ fibrils, it loses its capacity to strengthen synaptic plasticity. This explains why an increase in reelin expression in the brain may be beneficial,” explain the authors of the study.
The hypotheses from the work in vitro have been tested in vivo using experimental animals. This study is the first to demonstrate a neuroprotective effect of reelin in neurodegenerative disease and, in addition, offers a possible explanation for this protective role.
Yeast model reveals Alzheimer’s drug candidate and its mechanism of action
Using a yeast model of Alzheimer’s disease (AD), Whitehead Institute researchers have identified a drug that reduces levels of the toxic protein fragment amyloid-β (Aβ) and prevents at least some of the cellular damage caused when Ab accumulates in the brains of AD patients.
“We can use this yeast model to find small molecules that will address the underlying cellular pathologies of Alzheimer’s, an age-related disease whose burden will become even more significant as our population grows older,” says Kent Matlack, a former staff scientist in Whitehead Member Susan Lindquist’s lab. “We need a no-holds-barred approach to find effective compounds, and we need information about their mechanism of action quickly. Our work demonstrates that using a yeast model of Ab toxicity is a valid way to do this.”
The U.S. National Institute on Aging estimates that 5.1 million Americans may have AD, the most common form of dementia, which progressively robs patients of their memories, thinking, and reasoning skills. Research focused on the disease has been hampered by the affected cells’ location in the brain, where they cannot be studied until after an AD patient’s death. To explore the cellular processes compromised by AD, researchers in Lindquist’s lab created a yeast model, first described in the journal Science in 2011, that mimics in vivo the accumulation of Aβ that occurs in the human disease.
In the current research, which is described in this week’s issue of the journal Proceedings of the National Academy of Sciences (PNAS), a team of scientists in Lindquist’s lab used the yeast model to screen approximately 140,000 compounds to identify those capable of rescuing the cells from Aβ toxicity. One of the more promising classes of compounds has previously shown efficacy in animal models of AD and is about to complete a second phase II trial for AD. The mechanism by which the best-studied member of this class, clioquinol, targets Ab within the cell – where a large portion of it is produced in neurons – was unclear.
“Our work in the yeast model shows that clioquinol decreases the amount of Aβ in the cells by 90%,” says Daniel Tardiff, a scientist in Lindquist’s lab. “That’s a strong decrease, and it’s dose-dependent. I’ve tested a lot of compounds before, and I’ve never seen anything as dramatic.”
Clioquinol chelates copper, meaning that it selectively binds the metal. In many AD patients, Aβ aggregates have higher concentrations of copper and other metals than normal, healthy brain tissue. Biochemical experiments also show that copper makes Aβ more toxic.
With clioquinol’s chelation capabilities in mind, Tardiff and Matlack, co-authors of the PNAS paper, tested clioquinol’s effect on Aβ-expressing cells in the presence of copper. The drug dramatically increased the degradation of Aβ in a copper-dependent manner, and even restored the cellular protein-trafficking process known as endocytosis, which is disrupted in both the yeast model and in AD-affected neurons.
“The clioquinol probably has a slightly higher affinity for copper than Aβ does, but it is not a strong enough chelator to strip the cell’s normal metalloproteins of the copper they need,” says Matlack. “From what we’ve seen in the yeast model, we think the drug pulls the copper away from Aβ. That would alter Aβ’s structure and likely make it more susceptible to degradation, thus shortening its half-life in the cell.”
The results from clioquinol in yeast and the clinical potential of closely related compounds are promising. While these compounds are not yet ready to serve as AD drugs in the clinic, the identification of an AD-relevant compound and cellular pathology – along with the Lindquist lab’s previous identification of human AD risk alleles that reduce Ab toxicity in yeast – suggests that this discovery platform will continue to yield information and lead to more compounds with equal or greater effectiveness, some of which will hopefully make a difference in human disease.
“It is important to remember that this class of compounds was shown to work in mouse models and in a limited human trial,” says Lindqust, who is also a professor of biology at MIT and an investigator of the Howard Hughes Medical Institute. “We have validated the yeast model and shown that we can find such compounds at a speed that was inconceivable before—indeed we found some compounds that look even more effective.”
Cleveland Clinic identifies mechanism in Alzheimer’s-related memory loss
Cleveland Clinic researchers have identified a protein in the brain that plays a critical role in the memory loss seen in Alzheimer’s patients, according to a study to be published in the journal Nature Neuroscience and posted online today.
The protein – Neuroligin-1 (NLGN1) – is known to be involved in memory formation; this is the first time it’s been linked to amyloid-associated memory loss.
In Alzheimer’s disease, amyloid beta proteins accumulate in the brains of Alzheimer’s patients and induce inflammation. This inflammation leads to certain gene modifications that interrupt the functioning of synapses in the brain, leading to memory loss.
Using animal models, Cleveland Clinic researchers have discovered that during this neuroinflammatory process, the epigenetic modification of NLGN1 disrupts the synaptic network in the brain, which is responsible for developing and maintaining memories. Destroying this network can lead to the type of memory loss seen in Alzheimer’s patients.
"Alzheimer’s is a challenging disease that researchers have been approaching from all angles," said Mohamed Naguib, M.D., the Cleveland Clinic physician who lead the study. "This discovery could provide us with a new approach for preventing and treating Alzheimer’s disease."
Previous studies from this group of researchers have also identified a novel compound called MDA7, which can potentially stop the neuroinflammatory process that leads to the modification of NLGN1. Treatment with the compound restored cognition, memory and synaptic plasticity – a key neurological foundation of learning and memory – in an animal model. Significant preliminary work for the first-in-man study has been completed for MDA7 including in-vitro studies and preliminary clinical toxicology and pharmacokinetic work. The Cleveland Clinic plans to initiate Phase I human studies on the safety of this class of compounds in the near future.
Alzheimer’s disease is an irreversible, fatal brain disease that slowly destroys memory and thinking skills. About 5 million people in the United States have Alzheimer’s disease. With the aging of the population, and without successful treatment, there will be 16 million Americans and 106 million people worldwide with Alzheimer’s by 2050, according to the 2011 Alzheimer’s Disease Facts and Figures report from the Alzheimer’s Association.
(Source: eurekalert.org)
A new study from Uppsala University, Sweden, shows that one night of sleep deprivation increases morning blood concentrations of NSE and S-100B in healthy young men. These molecules are typically found in the brain. Thus, their rise in blood after sleep loss may indicate that a lack of snoozing might be conducive to a loss of brain tissue. The findings are published in the journal SLEEP.
Fifteen normal-weight men participated in the study. In one condition they were sleep-deprived for one night, while in the other condition they slept for approximately 8 hours.
“We observed that a night of total sleep loss was followed by increased blood concentrations of NSE and S-100B. These brain molecules typically rise in blood under conditions of brain damage. Thus, our results indicate that a lack of sleep may promote neurodegenerative processes”, says sleep researcher Christian Benedict at the Department of Neuroscience, Uppsala University, who lead the study.
“In conclusion, the findings of our trial indicate that a good night’s sleep may be critical for maintaining brain health”, says Christian Benedict.
Human Stem Cells Predict Efficacy of Alzheimer Drugs
Researchers from the University of Bonn use reprogrammed patient neurons for drug testing
Why do certain Alzheimer medications work in animal models but not in clinical trials in humans? A research team from the University of Bonn and the biomedical enterprise LIFE & BRAIN GmbH has been able to show that results of established test methods with animal models and cell lines used up until now can hardly be translated to the processes in the human brain. Drug testing should therefore be conducted with human nerve cells, conclude the scientists. The results are published by Cell Press in the journal “Stem Cell Reports”.
In the brains of Alzheimer patients, deposits form that consist essentially of beta-amyloid and are harmful to nerve cells. Scientists are therefore searching for pharmaceutical compounds that prevent the formation of these dangerous aggregates. In animal models, certain non-steroidal anti-inflammatory drugs (NSAIDs) were found to a reduced formation of harmful beta-amyloid variants. Yet, in subsequent clinical studies, these NSAIDs failed to elicit any beneficial effects.
"The reasons for these negative results have remained unclear for a long time", says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology of the University of Bonn and CEO of LIFE & BRAIN GmbH. "Remarkably, these compounds were never tested directly on the actual target cells – the human neuron", adds lead author Dr. Jerome Mertens of Prof. Brüstle’s team, who now works at the Laboratory of Genetics in La Jolla (USA). This is because, so far, living human neurons have been extremely difficult to obtain. However, with the recent advances in stem cell research it has become possible to derive limitless numbers of brain cells from a small skin biopsy or other adult cell types.
Scientists transform skin cells into nerve cells
Now a research team from the Institute for Reconstructive Neurobiology and the Department of Neurology of the Bonn University Medical Center together with colleagues from the LIFE & BRAIN GmbH and the University of Leuven (Belgium) has obtained such nerve cells from humans. The researchers used skin cells from two patients with a familial form of Alzheimer’s Disease to produce so-called induced pluripotent stem cells (iPS cells), by reprogramming the body’s cells into a quasi-embryonic stage. They then transformed the resulting so-called “jack-of-all-trades cells” into nerve cells.
Using these human neurons, the scientists tested several compounds in the group of non-steroidal anti-inflammatory drugs. As control, the researchers used nerve cells they had obtained from iPS cells of donors who did not have the disease. Both in the nerve cells obtained from the Alzheimer patients and in the control cells, the NSAIDs that had previously tested positive in the animal models and cell lines typically used for drug screening had practically no effect: The values for the harmful beta-amyloid variants that form the feared aggregates in the brain remained unaffected when the cells were treated with clinically relevant dosages of these compounds.
Metabolic processes in animal models differ from humans
"In order to predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells", concludes Prof. Brüstle’s colleague Dr. Philipp Koch, who led the study. Why do NSAIDs decrease the risk of aggregate formation in animal experiments and cell lines but not in human neurons? The scientists explain this with differences in metabolic processes between these different cell types. "The results are simply not transferable", says Dr. Koch.
The scientists now hope that in the future, testing of potential drugs for the treatment of Alzheimer’s disease will be increasingly conducted using neurons obtained from iPS cells of patients. “The development of a single drug takes an average of ten years”, says Prof. Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer medications could be greatly streamlined”.
(Source: www3.uni-bonn.de)
Study reveals how variant forms of APOE protein impact risk of Alzheimer’s disease
Carrying a particular version of the gene for apolipoprotein E (APOE) is the major known genetic risk factor for the sporadic, late-onset form of Alzheimer’s disease, but exactly how that variant confers increased risk has been controversial among researchers. Now an animal study led by Massachusetts General Hospital (MGH) investigators shows that even low levels of the Alzheimer’s-associated APOE4 protein can increase the number and density of amyloid beta (A-beta) brain plaques, characteristic neuronal damage, and the amount of toxic soluble A-beta within the brain in mouse models of the disease. Introducing APOE2, a rare variant that has been associated with protection from developing Alzheimer’s disease, into the brains of animals with established plaques actually reduced A-beta deposition, retention and neurotoxicity, suggesting the potential for gene-therapy-based treatment.
"Using a technique developed by our collaborators at the University of Iowa, we were able to get long-term expression of these human gene variants in the fluid that bathes the entire brain," says Bradley Hyman, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), senior author of the report in the Nov. 20 Science Translational Medicine. “Our results suggest that strategies aimed at decreasing levels of APOE4, the harmful form of the protein, and increasing concentrations of protective variant APOE2 could be helpful to patients.”
The association between the APOE4 variant and increased Alzheimer’s risk was first made more than 20 years ago. Subsequent research has established that carrying two copies of the harmful variant increases risk 12 times compared with having two copies of the more common form, APOE3. Inheriting the APOE2 variant, however, appears to cut the risk in half. The extremely rare gene variants that directly cause the familial forms of the disease all participate in the production and deposition of A-beta, but exactly how APOE variants contribute to the process has been poorly understood.
Secreted by certain brain cells, APOE is known to regulate cholesterol metabolism within the brain and can bind to A-beta peptides, suggesting that the different forms of the protein may affect whether and how toxic A-beta plaques form. While previous investigations into the protein’s effects have used either mice in which gene expression was knocked out or transgenic animals that expressed human gene variants throughout their lifetimes, the MGH-MIND-led study used a different approach to investigate the effects of introducing the variant forms of the protein into brains in which plaque formation had already begun. They directly injected into the cerebrospinal fluid of a mouse model of Alzheimer’s – adult animals in which plaques were well established – viral vectors carrying genes for one of the three APOE variants or a control protein.
Two month after the vectors had been injected, about 10 percent of the APOE in the brains of animals that received one of the variants was found to be the introduced human version. At five months after injection, examination of brain tissue revealed that the A-beta plaques in mice that received APOE4 injections were more numerous and significantly denser than those of mice receiving APOE2. The growth of plaques in animals receiving APOE3 was intermediate between that of the other two groups and similar to what was seen in control animals. Levels of A-beta in the blood of mice that received APOE2 were higher than in the other groups, suggesting that the protective variant had increased clearance of A-beta from the brain.
In a group of animals in which tiny implanted windows allowed direct imaging of brain tissue, the progression of A-beta plaque deposition was fastest in animals receiving APOE4 and slowest, sometimes even appearing to regress, in mice injected with APOE2. Signs of neuronal damage around plaques also varied depending on the APOE variant the animals received, and experiments in a different Alzheimer’s model in which plaques appear more slowly showed that injection of APOE4 increased levels of free, soluble A-beta in the fluid that bathes the brain.
"This study has allowed us to sort out, in mice, which effects of the different types of APOE were most important to variation in amyloid plaque deposition," says Eloise Hudry, PhD, of MGH-MIND, lead author of the Science Translational Medicine report. “Our results imply that APOE-based therapeutic approaches may help to alleviate the progression of Alzheimer’s disease. More study is needed to pursue that possibility and to investigate the potential use of this gene transfer technology to introduce other protective proteins into the brain.”
(Source: massgeneral.org)
Image: Mice lacking autophagy and with high levels of Aβ (right) have degenerated brain structures compared with normal mice (left).
The benefits of a spotless mind
Alzheimer’s disease is an age-related memory disorder characterized by the accumulation of clumps of the toxic amyloid-β (Aβ) protein fragment in the extracellular space around neurons in the brain. Drugs that help to ‘clean up’ cells by inducing autophagy—the degradation of unnecessary cellular components—are known to lower Aβ levels within cells and have been shown to rescue memory deficits in mice. A team of researchers including Per Nilsson and Takaomi Saido from the RIKEN Brain Science Institute have now found that autophagy also plays an important role in secreting Aβ from the cell into the extracellular space.
The researchers set out to investigate what would happen to extracellular Aβ aggregates, called plaques, when genetic methods were used to eliminate the autophagy process. They started with transgenic mice commonly used as a model for Alzheimer’s disease. These mice have high levels of Aβ and Aβ plaque accumulation in their brains, and display learning and memory deficits. Surprisingly, in genetically engineered variants of these mice lacking autophagy-related gene 7 (Atg7), which is required for normal autophagy, the researchers found fewer extracellular Aβ plaques in the brain; instead, the Aβ seemed to accumulate inside the neurons. Conversely, increasing the expression of the Atg7 protein in neurons grown in cell culture resulted in an increase in the release of Aβ from the cells into the tissue culture medium. The findings suggest that autophagy is required for the secretion of Aβ from neurons into the extracellular environment.
Mice with an elevated expression of Aβ but defective autophagy seemed to have degenerated brain structures, as well as sicker neurons—as defined by their expression of markers of cell death—and worse learning and memory functions than mice with high Aβ expression but normal autophagy. This result indicates that autophagy is important for maintaining normal neuronal function and cognition in Alzheimer’s disease. Moreover, because autophagy lowers Aβ levels within the cell, the researchers deduced that intracellular Aβ may be more toxic than extracellular Aβ with respect to inducing neuronal dysfunction and memory impairment.
The findings suggest that the effectiveness of therapeutic strategies for Alzheimer’s disease may be improved by targeting the elimination of intracellular Aβ deposits rather than extracellular plaques. “Intraneuronal Aβ accumulation is seen in early Alzheimer’s disease in humans, similar to what we found upon autophagy deletion in mice,” explains Nilsson. “Targeting this pool of Aβ may therefore offer a potential treatment for Alzheimer’s disease,” he says.
New Compound Inhibits Cognitive Impairment in Animal Models of Alzheimer’s Disease
The novel compound IRL-1620 may be useful in treating Alzheimer’s disease (AD) as it has been shown to prevent cognitive impairment and oxidative stress in animal models. This research is being presented at the 2013 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, the world’s largest pharmaceutical sciences meeting, in San Antonio, Nov. 10–14.
AD is a form of dementia that worsens over time, leading to a slow decline in cognitive functions and affecting memory, thinking, and behavior. More than 5 million Americans are living with AD, according to the Alzheimer’s Association.
Anil Gulati, M.D., Ph.D., FCP, and Seema Briyal, Ph.D., along with their colleagues from Midwestern University, administered Amyloid beta (Aβ), a main component of certain deposits located in AD patients’ brains, to normal and diabetic rats on days 1, 7, and 14. Spatial learning and memory were tested in a Morris water maze. The pool was divided into four equal quadrants, and an escape platform was hidden below the surface at a fixed location in one of the quadrants.
The rats had to find the platform within 60 seconds. The average time it took on day 4 for Aβ-treated rats to locate the platform was 55.05 seconds, though a majority of this group was not able to find it in the designated time. Aβ rats treated with IRL-1620 were able to locate the platform in 26.53 seconds, nearly half the time. After five days, Aβ rats treated with IRL-1620 showed a 60 percent improvement in learning and memory.
“Our research is based on the idea of using the Endothelin (ET) system in the treatment of AD,” said Gulati. “The ET system is traditionally known to play a role in the regulation of blood flow. This is important in the potential treatment of AD since disturbances in blood flow could damage the brain’s ability to clear damaging particles, leading to a build-up of toxic substances and cognitive impairment.”
The next stage of Gulati’s research is to further investigate the endothelin receptor type B’s mechanisms of neuroprotection and to look into possible resulting tissue changes following AD.
The FDA has approved five medications to treat the symptoms of AD. Current drugs help mask the symptoms but do not treat the underlying disease. A breakthrough Alzheimer’s treatment would target the underlying disease and stop or delay the cell damage that eventually leads to the worsening of symptoms.
(Source: newswise.com)
High Blood Pressure in Middle Age Versus Old Age May Better Predict Memory Loss
People in middle age who have a high blood pressure measure called pulse pressure are more likely to have biomarkers of Alzheimer’s disease in their spinal fluid than those with lower pulse pressure, according to research published in the November 13, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.
Pulse pressure is the systolic pressure, or the top number in a blood pressure reading, minus the diastolic, or the bottom number. Pulse pressure increases with age and is an index of the aging of the vascular system.
The study involved 177 people ages 55 to 100 with no symptoms of Alzheimer’s disease. Participants had their pulse pressure taken and lumbar punctures to obtain spinal fluid.
The study found that people who have higher pulse pressure are more likely to have the Alzheimer’s biomarkers amyloid beta, or plaques, and p-tau protein, or tangles, in their cerebral spinal fluid than those with lower pulse pressure. For every 10 point rise in pulse pressure, the average level of p-tau protein in the spinal fluid rose by 1.5 picograms per millileter. A picogram is one trillionth of a gram.
“These results suggest that the forces involved in blood circulation may be related to the development of the hallmark Alzheimer’s disease signs that cause loss of brain cells,” said study author Daniel A. Nation, PhD, of the VA San Diego Healthcare System.
The relationship was found in people age 55 to 70, but not in people age 70 to 100.
“This is consistent with findings indicating that high blood pressure in middle age is a better predictor of later problems with memory and thinking skills and loss of brain cells than high blood pressure in old age,” Nation said.
Study Examines Amyloid Deposition in Patients with Traumatic Brain Injury
Patients with traumatic brain injury (TBI) had increased deposits of β-Amyloid (Αβ) plaques, a hallmark of Alzheimer Disease (AD), in some areas of their brains in a study by Young T. Hong, Ph.D., of the University of Cambridge, England, and colleagues.
There may be epidemiological or pathophysiological (changes because of injury) links between TBI and AD, and Αβ plaques are found in as many as 30 percent of patients who die in the acute phase after a TBI. The plaques appear within hours of the injury and can occur in patients of all ages, according to the study background.
Researchers used imaging and brain tissue acquired during autopsies to examine Αβ deposition in patients with TBI. Researchers performed positron emission tomography (PET) imaging using carbon 11-labeled Pittsburgh Compound B ([11C]PIB), a marker of brain amyloid deposition, in 15 participants with a TBI and 11 healthy patients. Autopsy-acquired brain tissue was obtained from 16 people who had a TBI, as well as seven patients with a nonneurological cause of death.
The study’s findings indicate that patients with TBI showed increases in [11C]PIB binding, which may be a marker of Αβ plaque in some areas of the brain.
“The use of ([11C]PIB PET for amyloid imaging following TBI provides us with the potential for understanding the pathophysiology of TBI, for characterizing the mechanistic drivers of disease progression or suboptimal recovery in the subacute phase of TBI, for identifying patients at high risk of accelerated AD, and for evaluating the potential of antiamyloid therapies,” the authors conclude.
(Source: media.jamanetwork.com)