Tag Archives: Brain

A new study in the journal Nature Communications shows that cells normally associated with protecting the brain from infection and injury also play an important role in rewiring the connections between nerve cells. While this discovery sheds new light on the mechanics of neuroplasticity, it could also help explain diseases like autism spectrum disorders, schizophrenia, and dementia, which may arise when this process breaks down and connections between brain cells are not formed or removed correctly.

While the constant reorganization of neural networks – called neuroplasticity – has been well understood for some time, the basic mechanisms by which connections between brain cells are made and broken have eluded scientists.

Performing experiments in mice, the researchers employed a well-established model of measuring neuroplasticity by observing how cells reorganize their connections when visual information received by the brain is reduced from two eyes to one.

The researchers found that in the mice’s brains microglia responded rapidly to changes in neuronal activity as the brain adapted to processing information from only one eye. They observed that the microglia targeted the synaptic cleft – the business end of the connection that transmits signals between neurons. The microglia “pulled up” the appropriate connections, physically disconnecting one neuron from another, while leaving other important connections intact.

The researchers also pinpointed one of the key molecular mechanisms in this process and observed that when a single receptor – called P2Y12 – was turned off the microglia ceased removing the connections between neurons.

These findings may provide new insight into disorders that are the characterized by sensory or cognitive dysfunction, such as autism spectrum disorders, schizophrenia, and dementia. It is possible that when the microglia’s synapse pruning function is interrupted or when the cells mistakenly remove the wrong connections – perhaps due to genetic factors or because the cells are too occupied elsewhere fighting an infection or injury – the result is impaired signaling between brain cells.

Source: University of Rochester Medical Center (URMC)

Alzheimer Europe and Alzheimerforeningen are now accepting abstracts for the 26th Alzheimer Europe Conference, which will take place from October 31 – November 2, 2016, in Copenhagen, Denmark.

Abstracts for oral and poster presentations can be submitted in the following categories:

Dementia-friendly society – Involving people with dementia, Perceptions and image of dementia, Art and dementia, Dementia-friendly communities
Policies and Strategies – Dementia strategies, Legal issues, Care financing, Minority groups
Innovative care – Hospital care, Post-Diagnostic support, Residential care, End-of-life care
Medical aspects – Timely diagnosis, Risk factors and prevention of dementia, Behavioural and psychological aspects of dementia, Treatment of dementia

The call for abstracts will close on April 30, 2016. More information is available on their website.

The European Medicines Agency (EMA) has released draft revised guidelines on medicines for the treatment of Alzheimer’s disease and other types of dementias for a six-month public consultation.

EMA follows a multi-stakeholder approach to facilitate research and development of more effective medicines. The revised guidelines take into account comments received at EMA’s workshop on the clinical investigation of medicines for the treatment of Alzheimer’s disease in November 2014. This workshop brought together a wide range of stakeholders, including patient representatives, regulators, pharmaceutical industry and independent experts. The aim of the workshop was to ensure that during the revision of its guidelines, EMA would be able to consider the most up-to-date scientific developments in understanding and treating Alzheimer’s disease and views from experts in the field. The revised guidelines also build on EMA scientific advice provided for a number of specific development plans for Alzheimer’s disease in recent years, as well as the qualification of several biomarkers for the selection of patients in clinical trials.

The revised guideline specifically addresses the:

impact of new diagnostic criteria for Alzheimer’s disease, including early and even asymptomatic disease stages, on clinical trial design
choice of parameters to measure trial outcomes and the need for distinct assessment tools for the different disease stagesin Alzheimer’s (different signs and symptoms, differences in changes over time, severity)
potential use of biomarkers and their temporal relationship with the different phases of Alzheimer’s disease at different stages of medicine development (mechanism of action, use as diagnostic test, enrichment of study populations, stratification of subgroups, safety and efficacy markers etc.)
design of long-term efficacy and safety studies

Comments received during the consultation will be taken into account in the finalisation of the guideline.

Stakeholders are invited to send their comments by 31 July 2016. To learn more, visit the EMA website.

Source: EMA

Scientists have solved a longstanding problem with modeling Parkinson’s disease in animals. Using newfound insights, they improve both cell and animal models for the disease, which can propel research and drug development.

Parkinson’s disease is characterized by the appearance of protein clumps within neurons in the brain, called Lewy bodies. Reproducing Lewy bodies in animals in order to model the disease for research and drug screening has proven notoriously difficult, leaving a gap in Parkinson’s research and treatment. Scientists have now shown where the discrepancy between humans and animals lies. Using the knowledge, the scientists have produced cellular and mouse models that reproduce the evolution of Parkinson’s disease more accurately for both fundamental research and drug development. The work is published in PNAS.

In humans, Lewy bodies form when the brain produces twice the normal amount of alpha-synuclein. When mice, which are often used to model human diseases, are used to model Parkinson’s, they are genetically engineered to overproduce it. But human alpha-synuclein does not form fibrils and Lewy bodies when produced in mice.

Mice produce three types of their own synuclein, which are similar to human alpha-synuclein. Because of this, they are referred to as its “homologues”. The researchers found that human alpha-synuclein does not form Lewy bodies in mice because its homologues in the animal prevent it from doing so. This discovery explains why it is so difficult to model Parkinson’s disease in normal mice, which have all of their synuclein homologues. In other words, the key to successfully modeling the disease in mice is to genetically suppress their homologues of human alpha-synuclein.

Working off their genetically engineered mice and neuronal cultures, the team developed and characterized new models for Lewy bodies for the scientific and medical community. Hilal Lashuel expects that the new insights will advance the development of neuronal and in vivo models that reproduce features of Parkinson’s disease, and allow screening for new drugs. “We now have a very well-characterized model that offers a powerful tool for rapid screening of molecular pathways involved in Parkinson’s disease,” he says.

Source: École polytechnique fédérale de Lausanne

A study conducted on mice offers a new type of immunotherapy approach for treating Alzheimer’s disease. This involves amplifying a specific population of T lymphocytes that regulate immune and neuroinflammatory mechanisms that develop during the disease.

These results are published in the journal Brain.

In recent years, a body of substantive work has enabled the start of gaining further insight into complex immune and neuroinflammatory mechanisms associated with Alzheimer’s disease. The researchers offer further proof of concept on the efficacy of innovative immunotherapy strategy in mice that is based on an immunomodulation approach.

Researchers have shown, in earlier work with mice, that a specific population of T lymphocytes, known as T regulators (or Treg), modulated specific Ab peptide T lymphocytes that accumulate in the brains of sick people. Researchers chose to evaluate the effect of Treg cells on disease progression using a mouse model.

To do this, they either depleted or amplified Treg cells at the early stage of the disease. They found that a Treg deficiency accelerated the onset of cognitive disorders and was associated with a decrease in the presence of microglial cells in deposits of Ab peptide.

By contrast, prolonged Treg amplification using low doses of interleukin-2 injected intraperitoneally increases the microglial cell response and delays the onset of memory impairment.

This immunomodulation approach involving the injection of low doses of interleukin-2, already tested in some bone marrow transplant clinical protocols and for type 1 diabetes, now seems to be a new therapeutic strategy for Alzheimer’s disease. Researchers are already planning a pilot clinical trial in humans and are also considering the possibility of modulating some specific sub-populations of T lymphocytes to refine the response.

Source: Inserm

A team of researchers has discovered a previously unknown cellular defect in patients with idiopathic Parkinson’s disease, and identified a sequence of pathological events that can trigger or accelerate premature death of certain neurons in the brain seen in this disease.

Researchers discovered that the cells of people with idiopathic Parkinson’s disease have a previously unknown defect in the function of a specific PLA2g6 protein, causing dysfunction of calcium homeostasis that can determine whether some cells will live or die.

“Idiopathic or genetic dysfunction of calcium signaling triggers a sequence of pathological events leading to autophagic dysfunction, progressive loss of dopaminergic neurons and age-dependent impairment of vital motor functions typical for Parkinson’s disease,“ explained corresponding author Victoria Bolotina.

The findings were published in the journal Nature Communications.

Source: Boston University School of Medicine

Scientists have revealed that protein clumps associated with Alzheimer’s disease are also found in the brains of people who have had a head injury.

Although previous research has shown that these clumps, called amyloid plaques, are present shortly after a brain injury – this study shows the plaques are still present over a decade after the injury.

The findings may help explain why people who have suffered a serious brain injury appear to be at increased risk of dementia. Although extensive research now suggests major head injury increases dementia risk in later life, scientists do not know the biological changes that cause this effect.

In the research, published in the journal Neurology, the team studied nine patients with moderate to severe traumatic brain injuries. Many had sustained these in road traffic accidents, such as being hit by a car, between 11 months to 17 years prior to the study. The patient underwent a brain scan that used a technique that allows scientists to view amyloid plaques. These proteins are thought to be a hallmark of Alzheimer’s disease, and their formation may trigger other changes that lead to the death of brain cells.

The team also scanned the brains of healthy volunteers, and people with Alzheimer’s disease. The patients with head injury were found to have more amyloid plaques than the healthy volunteers, but fewer than those with Alzheimer’s disease.

In the head injury patients, the amyloid plaques were found to be centred mainly in two brain areas: the posterior cingulate cortex – a highly active area in the centre of the brain involved in controlling attention and memory, and the cerebellum – a region at the base of the brain involved in motor control and coordination.

In a second part of the study, the team assessed damage to so-called white matter. This is the ‘wiring’ of the brain, and enables brain cells to communicate with each other. The results showed that amyloid plaque levels in the posterior cingulate cortex were related to the amount of white matter damage, suggesting that injury to the brain’s wiring may be linked to the formation of amyloid plaques.

Source: Imperial College London

Scientists have discovered a mechanism which is responsible for the degeneration of Purkinje cells in the cerebellum in the neurodegenerative disease Spinocerebellar ataxia type 1. The results of their study open up new avenues for the future treatment of cerebellum-associated degenerative disorders.

Damage, degeneration or loss of neurons in the region of the brain that controls muscle coordination (cerebellum), results in ataxia. The symptoms include loss of voluntary coordination of muscle movements and the appearance of gait abnormality, loss of balance and speech problems. Cerebellar ataxias are progressive degenerative disorders which occur in adults either sporadically or can be inherited from parents. Unfortunately, the large majority of cerebellar ataxia cases are sporadic in nature and the causative mechanism for the development of ataxia remains largely unknown, which eventually hinders the development of therapy and negatively influences the quality of a patient’s life. However, both the sporadic and inherited cases of cerebellar ataxia exhibit common pathophysiological characteristics such as the specific degeneration of the main cerebellar neurons; the Purkinje cells. Therefore, the researchers set out to understand the potential mechanism involved in the development of ataxia and degeneration of Purkinje cells in Spinocerebellar ataxia type 1 (SCA1), a rare, incurable, inheritable neurodegenerative disease that can be modeled in mice.

A protein-based screening of Purkinje cells was performed to identify changes that occur in these neurons at the time of ataxia appearance. The team discovered widespread alterations in proteins which function at the synapse and identified a synaptic protein Homer-3 that is mainly present in Purkinje cell synapses to be reduced. Further, they found that Homer-3 decrease was related to the alteration in an important signaling pathway, mTORC1. This signaling pathway was responsible for regulating the expression of synaptic proteins such as Homer-3. The team discovered a cellular mechanism in the cerebellum of SCA1 mice that specifically targets the degeneration of Purkinje cells and the findings present a promising future therapeutic target. The study was published in the scientific journal Neuron.

Source: University of Bern

Researchers have discovered that an existing compound, previously tested for diabetes, offers hope for slowing Huntington’s Disease (HD) and its symptoms.

The study was published in Nature Medicine.

“We’re very excited by our pre-clinical testing of this compound (KD3010),” said Albert La Spada, MD, PhD, professor of pediatrics, cellular and molecular medicine and neurosciences at UC San Diego School of Medicine. “It improved motor function, reduced neurodegeneration and increased survival in a mouse model of Huntington’s disease and reduced toxicity in neurons generated from human HD stem cells.”

The discovery of the drug’s potential in HD builds upon more than a decade of research into the disorder’s underlying molecular pathology. Much of that work has centered on misfolded proteins, which are known to be key culprits in HD and several other neurodegenerative diseases.

At the cellular level, the drug improved mitochondrial energy production and helped mice get rid of the misfolded proteins. Since misfolded proteins also underlie Alzheimer’s, Parkinson’s and other neurodegenerative disorders, researchers hope that, if successful in HD, the compound can also be tested in other related neurological diseases.

Source: UC San Diego

A study has found that blocking a receptor in the brain responsible for regulating immune cells could protect against the memory and behaviour changes seen in the progression of Alzheimer’s disease.

It was originally thought that Alzheimer’s disease disturbs the brain’s immune response, but this latest study, published in the journal Brain, adds to evidence that inflammation in the brain can in fact drive the development of the disease. The findings suggest that by reducing this inflammation, progression of the disease could be halted.

The team hopes the discovery will lead to an effective new treatment for the disease, for which there is currently no cure.

The researchers used tissue samples from healthy brains and those with Alzheimer’s, both of the same age. The researchers counted the numbers of a particular type of immune cell, known as microglia, in the samples and found that these were more numerous in the brains with Alzheimer’s disease. In addition, the activity of the molecules regulating the numbers of microglia correlated with the severity of the disease.

The researchers then studied these same immune cells in mice which had been bred to develop features of Alzheimer’s. They wanted to find out whether blocking the receptor responsible for regulating microglia, known as CSF1R, could improve cognitive skills. They gave the mice oral doses of an inhibitor that blocks CSF1R and found that it could prevent the rise in microglia numbers seen in untreated mice as the disease progressed. In addition, the inhibitor prevented the loss of communication points between the nerve cells in the brain associated with Alzheimer’s, and the treated mice demonstrated fewer memory and behavioural problems compared with the untreated mice.

Importantly, the team found the healthy number of microglia needed to maintain normal immune function in the brain was maintained, suggesting the blocking of CSF1R only reduces excess microglia.

Source: University of Southampton