Monthly Archives: martie 2016

In the early stages of Alzheimer’s disease, patients are often unable to remember recent experiences. However, a new study suggests that those memories are still stored in the brain, they just can’t be easily accessed.

Researchers report in Nature that mice in the early stages of Alzheimer’s can form new memories just as well as normal mice but cannot recall them a few days later.

Furthermore, the researchers were able to artificially stimulate those memories using a technique known as optogenetics, suggesting that those memories can still be retrieved with a little help. Although optogenetics cannot currently be used in humans, the findings raise the possibility of developing future treatments that might reverse some of the memory loss seen in early-stage Alzheimer’s, the researchers say.

The researchers studied two different strains of mice genetically engineered to develop Alzheimer’s symptoms, plus a group of healthy mice.

All of these mice, when exposed to a chamber where they received a foot shock, showed fear when placed in the same chamber an hour later. However, when placed in the chamber again several days later, only the normal mice still showed fear. The Alzheimer’s mice did not appear to remember the foot shock.

The researchers then showed that while the mice cannot recall their experiences when prompted by natural cues, those memories are still there.

To demonstrate this, they first tagged the engram cells associated with the fearful experience with a light-sensitive protein called channelrhodopsin, using a technique they developed in 2012. Whenever these tagged engram cells are activated by light, normal mice recall the memory encoded by that group of cells. Likewise, when the researchers placed the Alzheimer’s mice in a chamber they had never seen before and shined light on the engram cells encoding the fearful experience, the mice immediately showed fear.

The researchers also showed that the engram cells of Alzheimer’s mice had fewer dendritic spines, which are small buds that allow neurons to receive incoming signals from other neurons.

Normally, when a new memory is generated, the engram cells corresponding to that memory grow new dendritic spines, but this did not happen in the Alzheimer’s mice. This suggests that the engram cells are not receiving sensory input from another part of the brain called the entorhinal cortex. The natural cue that should reactivate the memory — being in the chamber again — has no effect because the sensory information doesn’t get into the engram cells.

The researchers were also able to induce a longer-term reactivation of the “lost” memories by stimulating new connections between the entorhinal cortex and the hippocampus.

To achieve this, they used light to optogenetically stimulate entorhinal cortex cells that feed into the hippocampal engram cells encoding the fearful memory. After three hours of this treatment, the researchers waited a week and tested the mice again. This time, the mice could retrieve the memory on their own when placed in the original chamber, and they had many more dendritic spines on their engram cells.

However, this approach does not work if too large a section of the entorhinal cortex is stimulated, suggesting that any potential treatments for human patients would have to be very targeted. Optogenetics is very precise but too invasive to use in humans, and existing methods for deep brain stimulation — a form of electrical stimulation sometimes used to treat Parkinson’s and other diseases — affect too much of the brain.

Source: Anne Trafton, MIT News Office

Paper: „Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease”

Researchers have used a non-invasive method of observing how the process leading to Parkinson’s disease takes place at the nanoscale, and identified the point in the process at which proteins in the brain become toxic, eventually leading to the death of brain cells.

The results suggest that the same protein can either cause, or protect against, the toxic effects that lead to the death of brain cells, depending on the specific structural form it takes, and that toxic effects take hold when there is an imbalance of the level of protein in its natural form in a cell. The work could help unravel how and why people develop Parkinson’s, and aid in the search for potential treatments. The study is published in the journal Proceedings of the National Academy of Sciences.

Using super-resolution microscopy, researchers were able to observe the behaviour of different types of alpha-synuclein, a protein closely associated with Parkinson’s disease, in order to find how it affects neurons, and at what point it becomes toxic.

Parkinson’s disease is one of a number of neurodegenerative diseases caused when naturally occurring proteins fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. These amyloid deposits of aggregated alpha-synuclein, also known as Lewy bodies, are the hallmark of Parkinson’s disease.

Parkinson’s disease is the second-most common neurodegenerative disease worldwide (after Alzheimer’s disease). More than seven million people worldwide have the disease. Symptoms include muscle tremors, stiffness and difficulty walking. Dementia is common in later stages of the disease.

The researchers used different forms of alpha-synuclein and observed their behaviour in neurons from rats. They were then able to correlate what they saw with the amount of toxicity that was present.

They found that when they added alpha-synuclein fibrils to the neurons, they interacted with alpha-synuclein protein that was already in the cell, and no toxic effects were present.

The researchers then observed that by adding the soluble form of alpha-synuclein together with amyloid fibrils, the toxic effect of the former could be overcome. It appeared that the amyloid fibrils acted like magnets for the soluble protein and mopped up the soluble protein pool, shielding against the associated toxic effects.

The research shows how important it is to fully understand the processes at work behind neurodegenerative diseases, so that the right step in the process can be targeted.

Source: Adapted from materials provided by the University of Cambridge
„Nanoscopic insights into seeding mechanisms and toxicity of α-synuclein species in neurons”

Today the Lancet Neurology Commission released a major report detailing the state of research and patient care for Alzheimer´s disease and other dementias and providing recommendations for the future. The conclusion: A concerted effort and long-term economic commitment are critical to meeting the global challenge of Alzheimer’s disease and other dementias.

The comprehensive report, which was the result of a collaborative effort between more than 30 leading researchers from around the world, will also be presented to the European Parliament Commissioners today in Brussels.

The Lancet Neurology Commission, initiated by Lancet editors, is led by Professor Bengt Winblad of the Center for Alzheimer Research at the Karolinska Institutet in Sweden. Winblad is also a member of the JPND Scientific Advisory Board and was the coordinator of BIOMARKAPD, a JPND project on Biomarkers for Alzheimer’s disease and Parkinson’s disease. Three other members of the JPND Scientific Advisory Board, Prof. Martin Knapp (United Kingdom), Prof. Bruno Dubois (France), and Prof. Philip Scheltens (Netherlands), as well as the Chair of the JPND Management Board, Prof. Philippe Amouyel, participated as experts in this report. The commission was formed with the aim of providing expert recommendations and information to politicians and policymakers about Alzheimer´s disease and related dementias.

The report encompasses the fields of health economics, epidemiology, prevention, genetics, biology, diagnosis, treatment, care and ethics. To reduce the burden of dementia, the commission advocates that public governmental agencies form large multinational partnerships with academic centres and pharmaceutical companies to deploy capital resources and share risk.

„To defeat Alzheimer’s disease and other dementias, united actions are needed, not only within research, but also within the political arena on all levels,” said Winblad. „My hope is that our work will stimulate increased national and international collaboration.”

Alzheimer’s, the most common form of dementia, accounts for approximately 60 percent of cases. The most important risk factor is age, and as life expectancy increases, the number of people with dementia is also expected to rise. In 2015, almost 47 million individuals around the world were estimated to be affected. By 2030, the number is expected to reach 75 million. By 2050, up to 131 million people are expected to be burdened by the disease. So far, no treatment is available to effectively halt or reverse the disease.

Alzheimer’s disease and related disorders are one of the major targets of JPND, which as the largest global research initiative aimed at tackling the challenge of neurodegenerative diseases is cited in the report as an example of the sort of action needed to make meaningful progress. „To speed up progress even more, ” the report asserts, „this global collaboration must be extended to even more countries.”

For Winblad, the onus is now on governments to take action — and quickly: „What we need now is for the politicians to realise that this is a growing problem that already costs society tremendous amounts of money,” he said. „We need investments of resources in research in all areas involved in this disease, to find better drugs, but also to improve compassionate care and prevention.”

Using a drug compound created to treat cancer, neurobiologists have disarmed the brain’s response to the distinctive beta-amyloid plaques that are the hallmark of Alzheimer’s disease.

The researchers found that flushing away the abundant inflammatory cells produced in reaction to beta-amyloid plaques restored memory function in test mice. Their study showed that these cells, called microglia, contribute to the neuronal and memory deficits seen in this neurodegenerative disease. Results appear online in the journal Brain.

The neurobiologists treated Alzheimer’s disease model mice with a small-molecule inhibitor compound called pexidartinib, or PLX3397, which is currently being used in several phase 2 oncology studies and a phase 3 clinical trial to treat a benign neoplasm of the joints.

The inhibitor works by selectively blocking signaling of microglial surface receptors, known as colony-stimulating factor 1 receptors, which are necessary for microglial survival and proliferation in response to various stimuli, including beta-amyloid. This led to a dramatic reduction of these inflammatory cells, allowing for analysis of their role in Alzheimer’s. The researchers noted a lack of neuron death and improved memory and cognition in the pexidartinib-treated mice, along with renewed growth of dendritic spines that enable brain neurons to communicate.

Although the compound swept away microglia, the beta-amyloid remained, raising new questions about the part these plaques play in Alzheimer’s neurodegenerative process.

In healthy tissue, microglia act as the first and main form of immune defense in the central nervous system. But in a disease state, such as Alzheimer’s, microglia appear to turn against the healthy tissue they were originally assigned to protect, causing inflammation in the brain. The beta-amyloid plaques in brain areas related to Alzheimer’s disease are rich with these rogue microglia.

Source: University of California, Irvine

Researchers are studying the causes of premature ageing of neurons in Parkinson’s patients with a defective DJ1 (PARK7) gene. The genetic defect causes changes in the cellular metabolism meaning that neurons are subjected to oxidative stress and an increased immune response in the brain. The study has just been published in the scientific journal Neurobiology of Disease.

Parkinson’s disease, the second most common neurodegenerative disease, has genetic causes in 15% of cases. Premature ageing of dopaminergic neurons in the substantia nigra in the brain is the reason for the motor symptoms that characterise this disease. However, how this happens is not yet fully understood.

In the current study, researchers looking for the answer in metabolism investigated a specific form of Parkinson’s disease with a defective DJ1 gene and discovered that two key metabolic pathways are affected.

The research team was also able to show that mutations in the DJ1 gene can also negatively affect other cells in the brain. Microglial cells, which are responsible for the immune reaction in the brain, become ‘hyperactive’ when the DJ1 gene is defective.

Interestingly, the researchers were able to determine metabolic changes not only in the brain’s immune cells but also in the blood of Parkinson’s patients with mutant DJ1. This could lead to new diagnostic avenues in the future.

The next step will involve investigating how affected metabolic pathways can be influenced using drugs. The changes described in glutamine and serine metabolic processes could thus be used to develop novel approaches for treating Parkinson’s.

Source: University of Luxembourg

New research shows for the first time that PET scans can track the progressive stages of Alzheimer’s disease in cognitively normal adults, a key advance in the early diagnosis and staging of the neurodegenerative disorder.

In the process, the scientists also obtained important clues about two Alzheimer’s-linked proteins – tau and beta-amyloid – and how they relate to each other.

The findings, published in the journal Neuron, come from positron emission tomography (PET) of 53 adults. Five were young adults aged 20-26, 33 were cognitively healthy adults aged 64-90 and 15 were patients aged 53-77 who had been diagnosed with probable Alzheimer’s dementia.

PET scans are used to detect early signs of disease by looking at cellular-level changes in organs and tissue. The results of the scans in this study paralleled Braak neuropathological stages, which range from one to six, describing the degree of tau protein accumulation in the brain.

The findings also shed light on the nature of tau and amyloid protein deposits in the aging brain. For many years, the accumulation of beta amyloid plaques was considered the primary culprit in Alzheimer’s disease. Over the past decade, however, tau, a microtubule protein important in maintaining the structure of neurons, has emerged as a major player. When the tau protein gets tangled and twisted, its ability to support synaptic connections becomes impaired.

While a number of symptoms exist that signal Alzheimer’s disease, a definitive diagnosis has been possible only through an examination of the brain after the patient has died. The availability of amyloid imaging for the past decade has improved this situation, but how Alzheimer’s developed as a result of amyloid remains a mystery. Studies done in autopsies linked the development of symptoms to the deposition of the tau protein.

Through the PET scans, the researchers confirmed that with advancing age, tau protein accumulated in the medial temporal lobe — home to the hippocampus and the memory center of the brain.

The study revealed that higher levels of tau in the medial temporal lobe was associated with greater declines in episodic memory, the type of memory used to code new information. The researchers tested episodic memory by asking subjects to recall a list of words viewed 20 minutes earlier.

One question yet to be answered is why so many people have tau in their medial temporal lobe yet never go on to develop Alzheimer’s. Likewise, adults may have beta amyloid in their brains and yet be cognitively healthy.

While higher levels of tau in the medial temporal lobe was linked to more problems with episodic memory, it was when tau spread outside this region to other parts of the brain, such as the neocortex, that researchers saw more serious declines in global cognitive function. Significantly, they found that tau’s spread outside the medial temporal lobe was connected to the presence of amyloid plaques in the brain.

What the study does indicate is that tau imaging could become an important tool in helping to develop therapeutic approaches that target the correct protein — either amyloid or tau — depending on the disease stage.

Source: Sarah Yang, UC Berkeley

Protein aggregates are deemed to be one reason for the death of nerve cells in disorders such as Alzheimer’s or Huntington’s disease. As researchers report in the current issue of Nature, they have now decoded a new cellular mechanism for the development of aggregates. Missing stop signals in the production of proteins lead erroneously to long lysine chains at the end of the protein. This in turn blocks the ribosomes, the cell’s protein factory. Healthy cells detect blocked ribosomes and rapidly destroy useless proteins. If the necessary quality control machinery does not function properly, defective proteins accumulate and form toxic aggregates.

In order to be able to treat neurodegenerative disorders in future, researchers have for many years been studying the cellular causes for the death of nerve cells. A determining cause is believed to be protein deposits – aggregates of misfolded proteins.

In each cell, proteins perform vital functions, acting as small molecular machines. The mRNA contains a start signal, the information about the protein structure, a stop signal and, at the end, a poly(A) tail. If the blueprint is damaged, for example due to radiation or mutagenic substances, this can lead to the loss of this stop signal. As a result, once the protein has been manufactured in the ribosomes, the completed protein cannot be released. Instead, the poly(A) tail is interpreted as the blueprint and additional amino acids are attached. The lysine chain that is positively charged as a result blocks the protein factory and the manufacture of protein comes to a standstill.

Healthy cells have a very efficient quality control process when it comes to the manufacture of protein. Misfolded and useless proteins are selected, repaired or rapidly destroyed.

Using a mouse model, the researchers can now demonstrate the fatal consequences of a quality control malfunction. Animals with the relevant mutation show symptoms of advanced neurodegeneration and a restricted ability to move.

The protein aggregates that develop have a sticky surface and act as a seed. They ultimately also bind functioning proteins, which are free of defects and vital for the cell. As a result, the cell is destabilized and, in the long run, is damaged.

Source: Max Planck Institute of Biochemistry

The body has a variety of natural defences to protect itself against neurodegeneration, but as we age, these defences become progressively impaired and can get overwhelmed.

Researchers have identified a drug that targets the first step in the toxic chain reaction leading to the death of brain cells, suggesting that treatments could be developed to protect against Alzheimer’s disease, in a similar way to how statins are able to reduce the risk of developing heart disease.

The drug, which is an approved anti-cancer treatment, has been shown to delay the onset of Alzheimer’s disease, both in a test tube and in nematode worms. It has previously been suggested that statin-like drugs – which are safe and can be taken widely by those at risk of developing disease – might be a prospect, but this is the first time that a potential ‘neurostatin’ has been reported.

When the drug was given to nematode worms genetically programmed to develop Alzheimer’s disease, it had no effect once symptoms had already appeared. But when the drug was given to the worms before any symptoms became apparent, no evidence of the condition appeared, raising the possibility that this drug, or other molecules like it, could be used to reduce the risk of developing Alzheimer’s disease. The results are reported in the journal Science Advances.

By analysing the way the drug, called bexarotene, works at the molecular level, the international team of researchers, from the University of Cambridge, Lund University and the University of Groningen, found that it stops the first step in the molecular cascade that leads to the death of brain cells. This step, called primary nucleation, occurs when naturally occurring proteins in the body fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. This process also creates smaller clusters called oligomers, which are highly toxic to nerve cells and are thought to be responsible for brain damage in Alzheimer’s disease.

For the past two decades, researchers have attempted to develop treatments for Alzheimer’s that could stop the aggregation and proliferation of oligomers. However, these attempts have all failed, in part because there was not a precise knowledge of the mechanics of the disease’s development.

The researchers were able to determine what happens during each stage of the disease’s development, and also what might happen if one of those stages was somehow switched off.

The researchers assembled a library of more than 10,000 small molecules that interact in some way with amyloid-beta, a molecule that plays a vital role in Alzheimer’s disease. They first analysed molecules that were either drugs already approved for some other purpose, or drugs developed for Alzheimer’s disease or other similar conditions which had failed clinical trials.

The first successful molecule they identified was bexarotene, which is approved by the US Food and Drug Administration for the treatment of lymphoma. One of the key advances of the current work is that by understanding the mechanisms of how Alzheimer’s disease develops in the brain, the researchers were able to target

Earlier studies of bexarotene had suggested that the drug could actually reverse Alzheimer’s symptoms by clearing amyloid-beta aggregates in the brain, which received a great deal of attention. However, the earlier results, which were later called into question, were based on a completely different mode of action – the clearance of aggregates – than the one reported in the current study. By exploiting their novel approach, which enables them to carry out highly quantitative analysis of the aggregation process, the researchers have now shown that compounds such as bexarotene could instead be developed as preventive drugs, because its primary action is to inhibit the crucial first step in the aggregation of amyloid-beta.

Source: University of Cambridge

Scientists have developed a new optical technique to study how information is transmitted in the brains of mice. Using this method, they found that only a small portion of synapses — the connections between cells that control brain activity — may be active at any given time.

The study was published in the latest issue of Nature Neuroscience.

To obtain a detailed view of synaptic activity, the researchers developed a novel compound called fluorescent false neurotransmitter 200 (FFN200). When added to brain tissue or nerve cells from mice, FFN200 mimics the brain’s natural neurotransmitters and allows researchers to spy on chemical messaging in action.

Using a fluorescence microscope, the researchers were able to view the release and reuptake of dopamine — a neurotransmitter involved in motor learning, habit formation, and reward-seeking behavior — in individual synapses. When all the neurons were electrically stimulated in a sample of brain tissue, the researchers expected all the synapses to release dopamine. Instead, they found that less than 20 percent of dopaminergic synapses were active following a pulse of electricity.

“This particular study didn’t explain what’s causing most of the synapses to remain silent,” said David Sulzer, a co-author of the paper. “If we can work this out, we may learn a lot more about how alterations in dopamine levels are involved in brain disorders such as Parkinson’s disease, addiction, and schizophrenia.”

Source: Columbia University Medical Center

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a devastating progressive neurodegenerative disease that results in the death of motor neurons, the nerve cells that control muscles. Eventually, individuals with ALS will lose their ability to walk, move, swallow and breathe.

Until recently, the role of astrocytes, glial cells that normally support motor neurons, in motor neuron death has been a mystery, but new research sheds new light on molecular mechanisms responsible for motor neuron death in ALS. In a study published in Nature Medicine, researchers demonstrate the explicit loss of major histocompatibility complex I (MHCI) expression in the outer membrane of motor neurons in ALS, leading to motor neuron vulnerability to ALS astrocyte toxicity.

For each subtype of MHCI protein, there is a receptor that binds to it, much like a lock and key. If MCHI proteins are the keys, then killer inhibitory receptors (KIRs) are the locks. In their study, the researchers not only provide evidence of the protective effect of MHCI against astrocyte toxicity in ALS but also identify the killer inhibitory receptors (KIRs) associated with the specific subclass of MHCI (HLA-F) involved in human motor neurons.

According to the study, a dramatic loss of MHCI (HLA-F) from motor neurons is observed in the spinal cords of subjects affected by ALS. This finding is supported by evidence obtained in animal models and in vitro experiments using animal and human cells, which give insight on the protective nature of MHCI (HLA-F). Specifically, MHCI expression in the animal model was modulated using adeno-associated viral vector serotype 9 (AAV9), resulting in increased expression of MHCI and markedly extended survival.

The protective nature of MHCI (HLA-F) points to a potential translational target to delay the progression of ALS, since HLA-F expression may significantly impact disease progression in patients. In the in vitro experiments, human motor neurons expressing higher levels of HLA-F experienced reduced astrocyte toxicity. However, it remains to be seen whether or not this can be translated into a clinical trial and meaningful therapy for patients.

Source: Nationwide Children’s Hospital