Posts tagged tau protein
Articles and news from the latest research reports.
Reduction of tau protein improves symptoms in model of severe childhood epilepsy
Researchers at the Gladstone Institutes have shown that reducing brain levels of the protein tau effectively blocks the development of disease in a mouse model of Dravet syndrome, a severe intractable form of childhood epilepsy. This therapeutic strategy not only suppressed seizure activity and premature death, but also improved cognitive and behavioral abnormalities that can accompany this syndrome.
Previous studies from this group have shown that lowering tau levels reduces abnormal brain activity in models of Alzheimer’s disease, but this is the first demonstration that tau reduction may also be beneficial in intractable genetic epilepsy.
"It would really be wonderful if tau reduction turned out to be useful not only in Alzheimer’s disease, but also in other disabling neurological conditions for which there currently are no effective treatments," said senior author Lennart Mucke, MD, the director of the Gladstone Institute of Neurological Disease and a professor of Neurology and Neuroscience at the University of California, San Francisco. "We suspected that this approach might be beneficial in Dravet, but we couldn’t be sure because of the severity of this syndrome and the corresponding model. We are thrilled that our strategy was so effective, but a lot more work is needed to advance it into the clinic."
Dravet syndrome is one of the most challenging forms of childhood epilepsy, resulting from a specific genetic mutation that affects sodium channels in the brain. Frequent, relentless seizures are accompanied by cognitive impairments and behavioral problems similar to autism, and up to 20% of patients succumb to sudden death. Current treatments for Dravet syndrome are largely ineffective, making research into the disorder particularly urgent.
"I am especially excited about the improvements we observed in cognitive and behavioral dysfunctions because these abnormalities are particularly hard on the kids—and their parents," said first author Ania Gheyara, MD, PhD, a staff scientist at Gladstone who is also affiliated with the UCSF Department of Pathology. "Our hope is that this approach will be broadly applicable to many different types of epilepsy."
In the study, which was published online today in the Annals of Neurology, the scientists reduced the level of the protein tau by genetically engineering Dravet mouse models, “knocking out” the gene associated with tau production. The deletion of one copy of the gene resulted in substantial improvements in most symptoms, while deleting both copies eliminated them almost completely. This included a significant reduction in both spontaneous and heat-induced seizures. The latter were used to mimic the fever-related seizures that are often seen in the early stages of Dravet syndrome. Network activity in the brain was also normalized, providing additional support for the remarkable ability of tau reduction to suppress epileptic activity.
Additionally, tau reduction ameliorated the learning and memory deficits and behavioral abnormalities present in the Dravet mice, which may relate to the cognitive impairments and autism-like behaviors seen in the human condition.
"The next steps are to develop tau-lowering therapeutics that could be used in humans and to evaluate their safety and efficacy in preclinical studies," said Dr. Mucke, "objectives we are pursuing actively."
(Source: eurekalert.org)
Novel Protein Fragments May Protect Against Alzheimer’s
The devastating loss of memory and consciousness in Alzheimer’s disease is caused by plaque accumulations and tangles in neurons, which kill brain cells. Alzheimer’s research has centered on trying to understand the pathology as well as the potential protective or regenerative properties of brain cells as an avenue for treating the widespread disease.
Now Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of Tel Aviv University’s Sagol School of Neuroscience, has discovered novel protein fragments that have proven protective properties for cognitive functioning.
In a study published in the Journal of Alzheimer’s Disease, Prof. Gozes examined the protective effects of two newly discovered protein fragments in mice afflicted with Alzheimer’s disease-like symptoms. Her findings have the potential to serve as a pipeline for new drug candidates to treat the disease.
NAP time for Alzheimer’s
"Several years ago we discovered that NAP, a snippet of a protein essential for brain formation, which later showed efficacy in Phase 2 clinical trials in mild cognitive impairment patients, a precursor to Alzheimer’s," said Prof. Gozes. "Now, we’re investigating whether there are other novel NAP-like sequences in other proteins. This is the question that led us to our discovery."
Prof. Gozes’ research focused on the microtubule network, a crucial part of cells in our bodies. Microtubules act as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s, this network breaks down, hindering motor abilities and cognitive function.
"NAP operates through the stabilization of microtubules — tubes within the cell which maintain cellular shape. They serve as ‘train tracks’ for movement of biological material," said Prof. Gozes. "This is very important to nerve cells, because they have long processes and would otherwise collapse. In Alzheimer’s disease, these microtubules break down. The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell."
Down the tubes
In her new study, Prof. Gozes and her team looked at the subunit of the microtubule — the tubulin — and the protein TAU (tubulin-associated unit), important for assembly and maintenance of the microtubule. Abnormal TAU proteins form the tangles that contribute to Alzheimer’s; increased tangle accumulation is indicative of cognitive deterioration. Prof. Gozes decided to test both the tubulin and the TAU proteins for NAP-like sequences. After confirming NAP-like sequences in both tubulin subunits and in TAU, she tested the fragments in tissue cultures for nerve-cell protecting properties against amyloid peptides, the cause of plaque build up in Alzheimer patients’ brains.
"From the tissue culture, we moved to a 10-month-old transgenic mouse model with frontotemporal dementia-like characteristics, which exhibits TAU pathology and cognitive decline," said Prof. Gozes. "We tested one compound — a tubulin fragment — and saw that it protected against cognitive deficits. When we looked at the ‘dementia’-afflicted brain, there was a reduction in the NAP parent protein, but upon treatment with the tubulin fragment, the protein was restored to normal levels."
Prof. Gozes and her team also measured the brain-to-body mass ratio, an indicator of brain degeneration, and saw a significant decrease in the mouse model compared to normal mice. Following the introduction of the tubulin fragments, however, the mouse’s brain to body ratio returned to normal. “We clearly see here the protective effect of the treatment,” said Prof. Gozes. “We witnessed the restorative and protective effects of totally new protein fragments, derived from proteins critical to cell function, in tissue cultures and on animal models.”
(Image: Getty Images)
Role of Calcium in Familial Alzheimer’s Disease Clarified in Penn Study, Pointing to New Therapeutic Options
In 2008, researchers at the Perelman School of Medicine at the University of Pennsylvania showed that mutations in two proteins associated with familial Alzheimer’s disease (FAD) disrupt the flow of calcium ions within neurons. The two proteins interact with a calcium release channel in an intracellular compartment. Mutant forms of these proteins that cause FAD, but not the normal proteins, result in exaggerated calcium signaling in the cell.
Now, the same team, led by J. Kevin Foskett, PhD, chair of Physiology, and a graduate student, Dustin Shilling, has found that suppressing the hyperactivity of the calcium channels alleviated FAD-like symptoms in mice models of the disease. Their findings appear this week in the Journal of Neuroscience.
Current therapies for Alzheimer’s include drugs that treat the symptoms of cognitive loss and dementia, and drugs that address the pathology of Alzheimer’s are experimental. These new observations suggest that approaches based on modulating calcium signaling could be explored, says Foskett.
The two proteins, called PS1 and PS2 (presenilin 1 and 2), interact with a calcium release channel, the inositol trisphosphate receptor (IP3R), in the endoplasmic reticulum. Mutant PS1 and PS2 increase the activity of the IP3R, in turn increasing calcium levels in the cell. “We set out to answer the question: Is increased calcium signaling, as a result of the presenilin-IP3R interaction, involved in the development of familial Alzheimer’s disease symptoms, including dementia and cognitive deficits?” says Foskett. “And looking at the findings of these experiments, the answer is a resounding ‘yes.’”
Robust Phenomenon
Exaggerated intracellular calcium signaling is a robust phenomenon seen in cells expressing FAD-causing mutant presenilins, in both human cells in culture and in mice. The team used two FAD mouse models to look for these connections. Specifically, they found that reducing the expression of IP3R1, the dominant form of this receptor in the brain, by 50 percent, normalized the exaggerated calcium signaling observed in neurons of the cortex and hippocampus in both mouse models.
(Image caption: Amyloid-beta (antibody 12F4) and hyper-phosphorylated tau (antibody AT180) immunostaining of hippocampus from 18-month-old mice. Amyloid plaques (top row) and intracellular tau tangles (bottom row) in the 3xTg mouse were strongly reduced by genetic deletion of 50% of the IP3R1 in the 3xTg/Opt mouse. Wild-type (WT) and Opt mice expressing 50% of InsP3R exhibited no pathology. Credit: J. Kevin Foskett, PhD & Dustin Shilling, Perelman School of Medicine, University of Pennsylvania)
In addition, using 3xTg mice – animals that contain presenilin 1 with an FAD mutation, as well as expressed mutant human tau protein and APP genes — the team observed that the reduced expression of IP3R1 profoundly decreased amyloid plaque accumulation in brain tissue and the hyperphosphorylation of tau protein, a biochemical hallmark of advanced Alzheimer’s disease. Reduced expression of IP3R1 also rescued defective electrical signaling in the hippocampus, as well and memory deficits in the 3xTg mice, as measured by behavioral tests.
“Our results indicate that exaggerated calcium signaling, which is associated with presenilin mutations in familial Alzheimer’s disease, is mediated by the IP3R and contributes to disease symptoms in animals,” says Foskett. “Knowing this now, the IP3 signaling pathway could be considered a potential therapeutic target for patients harboring mutations in presenilins linked to AD.”
The ‘calcium dysregulation’ hypothesis
“The ‘calcium dysregulation’ hypothesis for inherited, early-onset familial Alzheimer’s disease has been suggested by previous research findings in the Foskett lab. Alzheimer’s disease affects as many as 5 million Americans, 5 percent of whom have the familial form. The hallmark of the disease is the accumulation of tangles and plaques of amyloid beta protein in the brain.
“The ‘amyloid hypothesis’ that postulates that the primary defect is an accumulation of toxic amyloid in the brain has long been used to explain the cause of Alzheimer’s”, says Foskett. In his lab’s 2008 Neuron study, cells that carried the disease-causing mutated form of PS1 showed increased processing of amyloid beta that depended on the interaction of the PS proteins with the IP3R. This observation links dysregulation of calcium inside cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer’s disease.
Clinical trials for AD have largely been directed at reducing the amyloid burden in the brain. So far, says Foskett, these trials have failed to demonstrate therapeutic benefits. One idea is that the interventions started too late in the disease process. Accordingly, anti-amyloid clinical trials are now underway using asymptomatic FAD patients because it is known that they will eventually develop the disease, whereas predicting who will develop the common form of AD is much less certain.
“There has been an assumption that FAD is simply AD with an earlier, more aggressive onset,” says Foskett. “However, we don’t know if the etiology of FAD pathology is the same as that for common AD. So the relevance of our findings for understanding common AD is not clear. What’s important, in my opinion, is to recognize that AD could be a spectrum of diseases that result in common end-stage pathologies. FAD might therefore be considered an orphan-disease, and it’s important to find effective treatments, specifically for these patients - ones that target the IP3R and calcium signaling.”
Engineering resilience in the brain
Penn researchers model neural structures on the smallest scales to better understand traumatic brain injury
Compared to the monumental machines of science, things like the International Space Station or the Large Hadron Collider, the human brain doesn’t look like much. However, this three-pound amalgam of squishy cells is one of the most complicated and complex structures in the known universe.
With hundreds of billions of neurons, each with its own inner world of organelles and molecular components, understanding the fundamental wiring of the brain is a major undertaking, one that has received a commitment of at least $100 million worth of federal funding from the National Science Foundation (NSF), the National Institutes of Health and the Defense Advanced Research Projects Agency.
And with all of the brain’s interconnected structures, protecting or repairing this complicated machine means thinking like an engineer.
"The idea is really quite simple," says Vivek Shenoy, an NSF-supported professor of materials science and engineering at the University of Pennsylvania’s School of Engineering and Applied Science. "All of the mechanical properties of cells come from their cytoskeleton and the molecules within it. They’re all reinforcing frames, like the frame in a building. Engineers design buildings and other structural objects to make sure they don’t fail, so it’s the same principle: structural engineering on a very, very small level."
Shenoy applies this approach to a problem very much in the public eye—traumatic brain injury. Even the mildest forms of TBI, better known as concussions, can do irreversible damage to the brain. More serious forms can be fatal.
With a background in mechanical engineering and materials science, one might think that Shenoy’s contribution to this problem involves designing new helmets or other safety devices. Instead, he and his colleagues are uncovering the fundamental math and physics behind one of the core mechanisms of the injury: swelling in axons caused by damage to internal structures known as microtubules. These neural “train tracks” transport molecular cargo from one end of a neuron to another; when the tracks break, the cargo piles up and produces bulges in the axons that are the hallmark of fatal TBIs.
Armed with a better understanding of the mechanical properties of these critical structures, Shenoy and his colleagues are laying the foundations for drugs that could one day bolster neurons’ reinforcing frames, making them more resilient when faced with a TBI-inducing impact.
Train tracks and crossties
The first step toward this understanding was resolving a paradox: Why were the microtubules, the stiffest elements of the axons, the parts that were breaking when loaded with the stress of a blow to the head?
A recent finding from Shenoy’s team shows that the answer rests with a critical brain protein known as tau, which is implicated in several neurodegenerative diseases, including Alzheimer’s. If microtubules are like train tracks, tau proteins are the crossties that hold them together. The protein’s elastic properties help explain why rapid movement of the brain, whether on a football field or a car crash, leads to TBI.
Shenoy’s colleague Douglas Smith, professor of neurosurgery in Penn’s Perelman School of Medicine and director of the Penn Center for Brain Injury and Repair, had previously studied the mechanical properties of axons, subjecting them to strains of different forces and speeds.
"What we saw is that with slow loading rates, axons can stretch up to at least 100 percent with no signs of damage," Smith said. "But at faster rates, axons start displaying the same swellings you see in the TBI patients. This process occurs even with relatively short stretches at fast rates."
To explain this rate-dependent response, Shenoy and Smith had to delve deeper inside the structure of microtubules. Based on Smith’s work, other biophysical modelers had previously accounted for the geometry and elastic properties of the axon during a stretching injury, but they did not have good data for representing tau’s role.
"You need to know the elastic properties of tau," Shenoy said, "because when you load the microtubules with stress, you load the tau as well. How these two parts distribute the stress between them is going to have major impact on the system as a whole."
Elastic properties
Shenoy and his colleagues had a sense of tau’s elastic properties but did not have hard numbers until a 2011 experiment from a Swiss and German research team physically stretched out lengths of tau by plucking it with the tip of an atomic force microscope.
"This experiment demonstrated that tau is viscoelastic," Shenoy said. "Like Silly Putty, when you add stress to it slowly, it stretches a lot. But if you add stress to it rapidly, like in an impact, it breaks."
This behavior is because the strands of tau protein are coiled up and bonded to themselves in different places. Pulled slowly, those bonds can come undone, lengthening the strand without breaking it.
"The damage in traumatic brain injury occurs when the microtubules stretch but the tau doesn’t, as they can’t stretch as far," Shenoy said. "If you’re in a situation where the tau doesn’t stretch, such as what happens in fast strain rates, then all the strain will transfer to the microtubules and cause them to break."
With a comprehensive model of the tau-microtubule system, the researchers were able to boil down the outcome of rapid stress loading to equations with only a handful of variables. This mathematical understanding allowed the researchers to produce a phase diagram that shows the dividing line between strain rates that leave permanent damage versus ones that are safe and reversible.
Next steps
Having this mathematical understanding of the interplay between tau and microtubules is only the beginning.
"Predicting what kind of impacts will cause these strain rates is still a complicated problem," Shenoy said. "I might be able to measure the force of the impact when it hits someone’s head, but that force then has to make its way down to the axons, which depends on a lot of different things.
"You need a multiscale model, and our work will be an input to those models on the smallest scale."
In the longer term, however, knowing the parameters that lead to irreversible damage could lead to better understanding of brain injuries and diseases and to new preventive measures. It may even be possible to design drugs that alter microtubule stability and elasticity of axons in traumatic brain injury; Smith’s group has demonstrated that treatment with the microtubule-stabilizing drug taxol reduced the extent of axon swellings and degeneration after injuries in which they are stretched.
Ultimately, insights on the molecular level will be inputs to a more comprehensive view of the brain and its many hierarchies of organizations.
"When you’re talking about something’s mechanical properties, stiffness is what comes to mind," Shenoy said. "Biochemistry is what determines that stiffness in the brain’s structures, but that’s only at the molecular level. Once you build it up and formulate things at the appropriate scale, protecting the brain becomes more of a structural engineering problem."
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)
Researchers Model a Key Breaking Point Involved in Traumatic Brain Injury
Even the mildest form of a traumatic brain injury, better known as a concussion, can deal permanent, irreparable damage. Now, an interdisciplinary team of researchers at the University of Pennsylvania is using mathematical modeling to better understand the mechanisms at play in this kind of injury, with an eye toward protecting the brain from its long-term consequences.
Their recent findings, published in the Biophysical Journal, shed new light on the mechanical properties of a critical brain protein and its role in the elasticity of axons, the long, tendril-like part of brain cells. This protein, known as tau, helps explain the apparent contradiction this elasticity presents. If axons are so stretchy, why do they break under the strain of a traumatic brain injury?
Tau’s own elastic properties reveal why rapid impacts deal permanent damage to structures within axons, when applying the same force more slowly causes them to safely stretch. This understanding can now be used to make computer models of the brain more realistic and potentially can be applied toward tau-related diseases, such as Alzheimer’s.
The team consists of Vivek Shenoy, professor of materials science and engineering in the School of Engineering and Applied Science, Hossein Ahmadzadeh, a member of Shenoy’s lab, and Douglas Smith, professor of neurosurgery in Penn’s Perelman School of Medicine and director of the Penn Center for Brain Injury and Repair.
“One of the main things you see in the brains of patients who have died because of a TBI is swellings along the axons,” Shenoy said. “Inside axons are microtubules, which act like tracks for transporting molecular cargo along the axon. When they break, there’s an interruption in the flow of this cargo and it starts to accumulate, which is why you get these swellings.”
Smith had previously studied the mechanical properties of axons as a whole. By patterning axons in culture in parallel tracts, Smith and his colleagues could apply a stretch to the axons at different forces and speeds and measure how they responded.
“What we saw is that with slow loading rates, axons can stretch up to at least 100 percent with no signs of damage,” Smith said. “But at faster rates, axons start displaying the same swellings you see in the TBI patients. This process occurs even with relatively short stretch at fast rates. So the rate at which stretch is applied is the important component, such as occurs during rapid movement of the brain and stretching of axons due to head impact from a fall, assault or automobile crash.”
This observation still did not explain to researchers why microtubules, the stiffest part of the axon, were the parts that were breaking. To solve that puzzle, the researchers had to delve even deeper into their structure.
Microtubules are closely packed together inside axons, somewhat like a bundle of straws. Binding the individual straws together is the protein tau. Other biophysical modelers had previously accounted for the geometry and elastic properties of the axon during a stretching injury based on Smith’s work but did not have good data for representing tau’s role in the overall behavior of the system when it is loaded with stress over different lengths of time.
“You need to know the elastic properties of tau,” Shenoy said, “because when you load the microtubules with stress, you load the tau as well. How these two parts distribute the stress between them is going to have major impact on the system as a whole.”
Shenoy and his colleagues had a sense of tau’s elastic properties but did not have hard numbers until a 2011 experiment from a Swiss and German research team physically stretched out lengths of tau by plucking it with the tip of an atomic force microscope.
“This experiment demonstrated that tau is viscoelastic,” Shenoy said. “Like Silly Putty, when you add stress to it slowly, it stretches a lot. But if you add stress to it rapidly, like in an impact, it breaks.”
This behavior is because the strands of tau protein are coiled up and bonded to themselves in different places. Pulled slowly, those bonds can come undone, lengthening the strand without breaking it.
“The damage in traumatic brain injury occurs when the microtubules stretch but the tau doesn’t, as they can’t stretch as far,” Shenoy said. “If you’re in a situation where the tau doesn’t stretch, such as what happens in fast strain rates, then all the strain will transfer to the microtubules and cause them to break.”
With a comprehensive model of the tau-microtubule system, the researchers were able to boil down the outcome of rapid stress loading to equations with only a handful of variables. This mathematical understanding allowed the researchers to produce a phase diagram that shows the dividing line between strain rates that leave permanent damage versus safe and reversible loading and unloading of stress.
“Predicting what kind of impacts will cause these strain rates is still a complicated problem,” Shenoy said. “I might be able to measure the force of the impact when it hits someone’s head, but that force then has to make its way down to the axons, which depends on a lot of different things.
“You need a multiscale model, and our work will be an input to those models on the smallest scale.”
In the longer term, knowing the parameters that lead to irreversible damage could lead to better understanding of brain injuries and diseases and to new preventive measures. It may even be possible to design drugs that alter microtubule stability and elasticity of axons in traumatic brain injury; Smith’s group has demonstrated that treatment with the microtubule-stabilizing drug taxol reduced the extent of axon swellings and degeneration after stretch injury.
“Intriguingly, it may be no coincidence that tau is also the same protein that forms neurofibrillary tangles, one of the hallmark brain pathologies of chronic traumatic encephalopathy, or CTE, which is linked to a history of concussions and higher levels of TBI,” said Smith. “Uncovering the role of tau at the time of trauma may provide insight into how it is involved in long-term degenerative processes.”
Potential biomarkers for the diagnosis of Alzheimer’s disease
Drugs that modify DNA structure may be beneficial for treating Alzheimer’s Disease
In a study published this week in Nature Neuroscience, Bess Frost, PhD, and co-authors, identify abnormal expression of genes, resulting from DNA relaxation, that can be detected in the brain and blood of Alzheimer’s patients.
The protein tau is involved in a number of neurodegenerative disorders, including Alzheimer’s disease. Previous studies have implicated DNA damage as a cause of neuron, or cell, death in Alzheimer’s patients. Given that DNA damage can change the structure of DNA within cells, the researchers examined changes in DNA structure in tau-induced neurodegeneration. They used transgenic flies and mice expressing human tau to show that DNA is more relaxed in tauopathy. They then identified that the relaxation of tightly wound DNA and resulting abnormal gene expression are central events that cause neurons to die in Alzheimer’s disease.
The authors write, “Our work suggests that drugs that modify DNA structure may be beneficial for treating Alzheimer’s Disease.” The authors recommend, “A greater understanding of the pathway of DNA relaxation in tauopathies will allow us to identify the optimal target and explore the therapeutic potential of epigenetic-based drugs.”
(Source: eurekalert.org)
Researchers discover an epigenetic lesion in the hippocampus of Alzheimer’s patients
Alzheimer’s disease can reach epidemic range in the coming decades, by the increasing average age of society. There are two key issues for Alzheimer’s disease: there is currently no effective treatment and it has been described very few associated genetic changes (mutations) which reduces the number of targets for future therapies.
Alzheimer’s disease
Pathologically, Alzheimer’s disease is characterized by the accumulation of protein deposits in the brain of patients. These deposits are formed by plates of a protein called amyloid-beta and rolled tangles of tau protein. The root cause of these lesions in most cases is unknown, but specific alterations in regulating genes expression might be involved.
Today, the prestigious international journal in neurology Hippocampus publishes an article led by Manel Esteller, Director of Epigenetics and Cancer Biology, Institute of Biomedical Research of Bellvitge (IDIBEL), ICREA researcher and Professor of Genetics at the University of Barcelona, with the collaboration of the Institute of Neuropathology IDIBELL led by Isidre Ferrer, demonstrating for the first time the existence of an epigenetic lesion in the hippocampus of the brain of patients with Alzheimer.
Switches in the hippocampus
"We first started studying 30,000 molecular switches that turn on and off genes in the hippocampal region in the brains of Alzheimer patients in different stages of disease and compared with that of healthy patients of the same age. We note that dusp22 gene switches off (methylates) as the disease advances" explained Manel Esteller, director of the study.
"But more importantly" continues "was the discovery that this gene regulates tau protein. Perhaps therefore the accumulation of tau protein produced in the brain of patients with Alzheimer results from dusp22 epigenetic inactivation".
According Esteller “the finding is relevant not only to determine the causes of the disease, but also to test potential treatments in the future to act on these epigenetic molecular switches”.
Fluorescent compounds allow clinicians to visualize Alzheimer’s disease as it progresses
What if doctors could visualize all of the processes that take place in the brain during the development and progression of Alzheimer’s disease? Such a window would provide a powerful aid for diagnosing the condition, monitoring the effectiveness of treatments, and testing new preventive and therapeutic agents. Now, researchers reporting in the September 18 issue of the Cell Press journal Neuron have developed a new class of imaging agents that enables them to visualize tau protein aggregates, a pathological hallmark of Alzheimer’s disease and related neurodegenerative disorders, directly in the brains of living patients.
In the brains of patients with Alzheimer’s disease, tau proteins aggregate together and become tangled, while fragments of another protein, called amyloid beta, accumulate into deposits or plaques. Tau tangles are not only considered an important marker of neurodegeneration in Alzheimer’s disease but are also a hallmark of non-Alzheimer’s neurodegenerative disorders, tauopathies that do not involve amyloid beta plaques. While imaging technologies have been developed to observe the spread of amyloid beta plaques in patients’ brains, tau tangles were previously not easily monitored in the living patient.
In this latest research in mice and humans, investigators developed fluorescent compounds that bind to tau (called PBBs) and used them in positron emission tomography (PET) tests to correlate the spread of tau tangles in the brain with moderate Alzheimer’s disease progression. “PET images of tau accumulation are highly complementary to images of senile amyloid beta plaques and provide robust information on brain regions developing or at risk for tau-induced neuronal death,” says senior author Dr. Makoto Higuchi, of the National Institute of Radiological Sciences in Japan. “This is of critical significance, as tau lesions are known to be more intimately associated with neuronal loss than senile plaques.”
The advance may also be helpful for diagnosing, monitoring, and treating other neurological conditions because tau tangles are not limited to Alzheimer’s disease but also play a role in various types of dementias and movement disorders.
Stress-related protein speeds progression of Alzheimer’s disease
A stress-related protein genetically linked to depression, anxiety and other psychiatric disorders contributes to the acceleration of Alzheimer’s disease, a new study led by researchers at the University of South Florida has found.
The study is published online today in the Journal of Clinical Investigation.
When the stress-related protein FKBP51 partners with another protein known as Hsp90, this formidable chaperone protein complex prevents the clearance from the brain of the toxic tau protein associated with Alzheimer’s disease.
Under normal circumstances, tau helps make up the skeleton of our brain cells. The USF study was done using test tube experiments, mice genetically engineered to produce abnormal tau protein like that accumulated in the brains of people with Alzheimer’s disease, and post-mortem human Alzheimer’s brain tissue.
The researchers report that FKBP51 levels increase with age in the brain, and then the stress-related protein partners with Hsp90 to make tau more deadly to the brain cells involved in memory formation.
Hsp90 is a chaperone protein, which supervises the activity of tau inside nerve cells. Chaperone proteins typically help ensure that tau proteins are properly folded to maintain the healthy structure of nerve cells.
However, as FKBP51 levels rise with age, they usurp Hsp90’s beneficial effect to promote tau toxicity.
“We found that FKB51 commandeers Hsp90 to create an environment that prevents the removal of tau and makes it more toxic,” said the study’s principal investigator Chad Dickey, PhD, associate professor of molecular medicine at the USF Health Byrd Alzheimer’s Institute. “Basically, it uses Hsp90 to produce and preserve the bad tau.”
The researchers conclude that developing drugs or other ways to reduce FKB51 or block its interaction with Hsp90 may be highly effective in treating the tau pathology featured in Alzheimer’s disease, Parkinson’s disease dementia and several other disorders associated with memory loss.
A previous study by Dr. Dickey and colleagues found that a lack of FKBP51 in old mice improved resilience to depressive behavior.