Tag Archives: Research

For years, neuroscientists have puzzled over how two abnormal proteins, called amyloid and tau, accumulate in the brain and damage it in Alzheimer’s disease (AD). Which one is the driving force behind dementia? The answer: both of them, according to a new study.

In the journal Molecular Psychiatry, researchers report for the first time evidence that the interaction between amyloid and tau proteins drives brain damage in cognitively intact individuals.

”We specifically found that both proteins mutually enhance their individual toxic effects and cause a brain dysfunction considered to be a signature of AD. This finding challenges previous polarized theories that a single protein abnormality was the major driving force of disease progression,” explained the study’s leader, Dr. Pedro Rosa-Neto, a clinician scientist at the Douglas Mental Health University Institute and assistant professor of Neurology, Neurosurgery and Psychiatry at McGill University.
This research also points toward new potential therapeutic strategies to mitigate the progression of AD.

”Until now, therapeutic clinical trials have targeted a single pathological process. Our result paves the way for new therapeutic strategies for prevention or stabilization of AD. For example, combination therapies should be used simultaneously against both amyloid and tau protein accumulation”, says Dr. Tharick A. Pascoal, the study’s first author.

The researchers analyzed the performances of 120 cognitively intact individuals over two years (equal gender distribution; average age 75). By measuring amyloid levels using PET scans and tau proteins through cerebrospinal fluid analysis, the researchers were able to identify the patients at risk for brain damage associated with AD.

Source: Reprinted from materials provided by the McGill University.

Paper: “Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease“

A new study published in Proceedings of the National Academy of Sciences has discovered that a protein called IL-33 can reverse Alzheimer’s disease-like pathology and cognitive decline in mice.

“IL-33 is a protein produced by various cell types in the body and is particularly abundant in the central nervous system (brain and spinal cord),” explained Professor Eddy Liew, Fellow of the Royal Society, who co-directed the research. “We found that injection of IL-33 into aged APP/PS1 mice rapidly improved their memory and cognitive function to that of the age-matched normal mice within a week.”

The hallmarks of Alzheimer’s include the presence of extracellular amyloid plaque deposits and the formation of neurofibrillary tangles in the brain. During the course of the disease, ‘plaques’ and ‘tangles’ build up, leading to the loss of connections between nerve cells, and eventually to nerve cell death and loss of brain tissue.‌

IL-33 appears to work by mobilising microglia (immune cells in the brain) to surround the amyloid plagues, take them up and digest them and reduces the number and size of the plaques. IL-33 does so by inducing an enzyme called neprilysin, which is known to degrade soluble amyloid.

In addition, the IL-33 treatment worked by inhibiting the inflammation in the brain tissue, which has been shown earlier to potentiate plaque and tangle formation. Therefore IL-33 not only helps to clear the amyloid plague already formed but also prevent the deposition of the plaques and tangles in the first place.‌‌

Professor Liew added: “The relevance of this finding to human Alzheimer’s is at present unclear. But there are encouraging hints. For example, previous genetic studies have shown an association between IL-33 mutations and Alzheimer’s disease in European and Chinese populations. Furthermore, the brain of patients with Alzheimer’s disease contains less IL-33 than the brain from non-Alzheimer’s patients.

“Exciting as it is, there is some distance between laboratory findings and clinical applications. There have been enough false ‘breakthroughs’ in the medical field to caution us not to hold our breath until rigorous clinical trials have been done. We are just about entering Phase I clinical trial to test the toxicity of IL-33 at the doses used. Nevertheless, this is a good start.”

 

Source: Reprinted from materials provided by the University of Glasgow.

Paper: “IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline“

While research has identified hundreds of genes required for normal memory formation, genes that suppress memory are of special interest because they offer insights into how the brain prioritizes and manages all of the information, including memories, that it takes in every day. These genes also provide clues for how scientists might develop new treatments for cognitive disorders such as Alzheimer’s disease.

Scientists have identified a unique memory suppressor gene in the brain cells of Drosophila, the common fruit fly, in a study published in the journal Neuron.

The researchers screened approximately 3,500 Drosophila genes and identified several dozen new memory suppressor genes that the brain has to help filter information and store only important parts. One of these suppressor genes, in particular, caught their attention.

“When we knocked out this gene, the flies had a better memory—a nearly two-fold better memory,” said Ron Davis, chair of the Department of Neuroscience at The Scripps Research Institute and leader of the study. “The fact that this gene is active in the same pathway as several cognitive enhancers currently used for the treatment of Alzheimer’s disease suggests it could be a potential new therapeutic target.”

When the scientists disabled this gene, known as DmSLC22A, flies’ memory of smells (the most widely studied form of memory in this model) was enhanced—while overexpression of the gene inhibited that same memory function.

“Memory processes and the genes that make the brain proteins required for memory are evolutionarily conserved between mammals and fruit flies,” said Research Associate Ze Liu, co-first author of the study. “The majority of human cognitive disease-causing genes have the same functional genetic counterparts in flies.”

The gene in question belongs to a family of “plasma membrane transporters,” which produce proteins that move molecules, large and small, across cell walls. In the case of DmSLC22A, the new study indicates that the gene makes a protein involved in moving neurotransmitter molecules from the synaptic space between neurons back into the neurons. When DmSLC22A functions normally, the protein removes the neurotransmitter acetylcholine from the synapse, helping to terminate the synaptic signal. When the protein is missing, more acetylcholine persists in the synapse, making the synaptic signal stronger and more persistent, leading to enhanced memory.

“DmSLC22A serves as a bottleneck in memory formation,” said Research Associate Yunchao Gai, the study’s other co-first author. “Considering the fact that plasma transporters are ideal pharmacological targets, drugs that inhibit this protein may provide a practical way to enhance memory in individuals with memory disorders.”

The next step, Davis added, is to develop a screen for inhibitors of this pathway that, independently or in concert with other treatments, may offer a more effective way to deal with the problems of memory loss due to Alzheimer’s and other neurodegenerative diseases.

“One of the major reasons for working with the fly initially is to identify brain proteins that may be suitable targets for the development of cognitive enhancers in humans,” said Davis. “Otherwise, we would be guessing in the dark as to which of the more than 23,000 human proteins might be appropriate targets.”

Source: Reprinted from materials provided by Eric Sauter at The Scripps Research Institute.

Paper: “Drosophila SLC22A Transporter Is a Memory Suppressor Gene that Influences Cholinergic Neurotransmission to the Mushroom Bodies.”

A study appearing in the journal Neuron suggests there may be a new way to change the damaging course of Huntington’s disease.

Neurobiologists have shown that reducing the aberrant accumulation of a particular form of the mutant Huntingtin protein corresponds to improvement in symptoms and neuroinflammation in HD mice.

They showed this by targeting and modulating levels of PIAS1 — a protein implicated in cancer and other diseases — which they found led to the reduction of the mutant Huntington protein. The work suggests that changing levels of the PIAS1 protein and targeting this pathway could have a benefit to disease.

Source: Reprinted from materials provided by the University of California, Irvine.

Paper: “PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes In Vivo”

Researchers have shown how brain connections, or synapses, are lost early in Alzheimer’s disease and demonstrated that the process starts — and could potentially be halted — before telltale plaques accumulate in the brain. Their work, published online by Science, suggests new therapeutic targets to preserve cognitive function early in Alzheimer’s disease.

The researchers show in multiple Alzheimer’s mouse models that mechanisms similar to those used to “prune” excess synapses in the healthy developing brain are wrongly activated later in life. By blocking these mechanisms, they were able to reduce synapse loss in the mice.

Currently, there are five FDA-approved drugs for Alzheimer’s, but these only boost cognition temporarily and do not address the root causes of cognitive impairment in Alzheimer’s. Many newer drugs in the pipeline seek to eliminate amyloid plaque deposits or reduce inflammation in the brain, but the new research from Boston Children’s suggests that Alzheimer’s could be targeted much earlier, before these pathologic changes occur.

“Synapse loss is a strong correlate of cognitive decline,” says Beth Stevens, assistant professor in the Department of Neurology at Boston Children’s, senior investigator on the study and a recent recipient of the MacArthur “genius” grant. “We’re trying to go back to the very beginning and see how synapse loss starts.”

The researchers looked at Alzheimer’s — a disease of aging — through an unusual lens: normal brain development in infancy and childhood. Through years of research, the Stevens lab has shown that normal developing brains have a process to “prune” synapses that aren’t needed as they build their circuitry.

“Understanding a normal developmental process deeply has provided us with novel insight into how to protect synapses in Alzheimer’s and potentially a host of other diseases,” says Stevens, noting that synapse loss also occurs in frontotemporal dementia, Huntington’s disease, schizophrenia, glaucoma and other conditions.

In the Alzheimer’s mouse models, the team showed that synapse loss requires the activation of a protein called C1q, which “tags” synapses for elimination. Immune cells in the brain called microglia then “eat” the synapses — similar to what occurs during normal brain development. In the mice, C1q became more abundant around vulnerable synapses before amyloid plaque deposits could be observed.

When Stevens and colleagues blocked C1q, a downstream protein called C3, or the C3 receptor on microglia, synapse loss did not occur.

“Microglia and complement are already known to be involved in Alzheimer’s disease, but they have been largely regarded as a secondary event related to plaque-related neuroinflammation, a prominent feature in progressed stages of Alzheimer’s,” notes Soyon Hong, the Science paper’s first author. “Our study challenges this view and provides evidence that complement and microglia are involved much earlier in the disease process, when synapses are already vulnerable, and could potentially be targeted to preserve synaptic health.”

A human form of the antibody Stevens and Hong used to block C1q, known as ANX-005, is in early therapeutic development with Annexon Biosciences (San Francisco) and is being advanced into the clinic. The researchers believe it has potential to be used someday to protect against synapse loss in a variety of neurodegenerative diseases.

“One of the things this study highlights is the need to look for biomarkers for synapse loss and dysfunction,” says Hong. “As in cancer, if you treat people at a later stage of Alzheimer’s, it may already be too late.”

The researchers also found that the beta-amyloid protein, C1q and microglia work together to cause synapse loss in the early stages of Alzheimer’s. The oligomeric form of beta-amyloid (multiple units of beta-amyloid strung together) is already known to be toxic to synapses even before it forms plaque deposits, but the study showed that C1q is necessary for this effect. The converse was also true: microglia engulfed synapses only when oligomeric beta-amyloid was present.

Source: Reprinted from materials provided by Boston Children’s Hospital
Paper: “Complement and microglia mediate early synapse loss in Alzheimer mouse models”

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