Neuroscience
Month
Researchers have overcome a major challenge to treating brain diseases by engineering an experimental molecular therapy that crosses the blood-brain barrier to reverse neurological lysosomal storage disease in mice.
Posted online in PNAS Early Edition on Feb. 4, the study was led by scientists at Cincinnati Children’s Hospital Medical Center.
“This study provides a non-invasive procedure that targets the blood-brain barrier and delivers large-molecule therapeutic agents to treat neurological lysosomal storage disorders,” said Dao Pan, PhD, principal investigator on the study and researcher in the Cancer and Blood Diseases Institute at Cincinnati Children’s. “Our findings will allow the development of drugs that can be tested for other brain diseases like Parkinson’s and Alzheimer’s.”
The scientists assembled the large molecular agents by merging part of a fatty protein called apolipoprotein E (apoE) with a therapeutic lysosomal enzyme called a-L-idurondase (IDUA). Naming the agents IDUAe1 and IDUAe2, researchers used them initially to treat laboratory cultured human cells of the disease mucopolysaccharidosis type I (MPS I). They also tested the agents on mouse models of MPS I.
MPS I is one of the most common lysosomal storage diseases to affect the central nervous system, which in severe form can become Hurler syndrome. In humans, patients can suffer from hydrocephalus, learning delays and other cognitive deficits. If not treated, many patients die by age 10.
Lysosomes are part of a cell’s internal machinery, serving as a waste disposal system that helps rid cells of debris to retain normal function. In lysosomal storage diseases like MPS I, enzymes needed to dissolve debris are missing, allowing debris to build up in cells until they malfunction.
In MPS I, cells lack the IDUA enzyme, allowing abnormal accumulation of a group of large molecules called glycosaminoglycans in the brain and other organs. Researchers in the current study used the new therapeutic procedure to deliver IDUA to brain cells. But first they had to successfully engineer the therapy to carry IDUA through the blood-brain barrier to diseased brain cells.
The blood-brain barrier is a physiological blockade that alters the permeability of tiny blood vessels called capillaries in the brain. Its purpose is to protect the brain by preventing certain drugs, pathogens and other foreign substances from entering brain tissues. The barrier has also been a persistent roadblock to treating brain disease with drugs.
The scientists experimented with a set of derivative components of the fatty protein apoE, which binds to fat receptors on endothelial cells that form the inside surface of capillaries in the blood-brain barrier. They discovered that tagging some of the apoE components to the IDUA enzyme allowed the modified protein to attach to endothelial cells and cross through the cells to reach brain tissues.
Researchers injected experimental IDUAe1 into the tail veins of MPS I mouse models. The tests showed that – unlike currently available un-modified enzyme treatments – the modified enzyme penetrated the blood-brain barrier and entered brain neurons and astrocytes in a dose-dependent manner.
The researchers also reported that brain cells in the treated mice exhibited normalized levels of the glycosaminoglycans and the lysosomal enzyme beta-hexosaminidase. With continued treatment through hematopoietic stem cell gene therapy, normalized levels persisted until the end of a five-month observation period, researchers said.
The scientists are continuing their preclinical studies to further verify the use of the experimental IDUA-based agents for treating MPS I, cautioning that results in laboratory mice may face additional challenges when translating to clinical application in humans. Researchers are also testing whether the large-molecule therapeutic procedure used in the current study can be leveraged to develop other neurotherapeutic agents that cross the blood-brain barrier.
A research team in Israel has devised a novel approach to identifying the molecular basis for designing a drug that might one day decrease the risk diabetes patients face of developing Alzheimer’s disease. The team will present its work at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.
A recent study suggests that people who suffer from type 2 diabetes face twice the risk of developing Alzheimer’s disease later in life compared to those who do not have diabetes. The link these diseases share relates to the formation of two types of peptide deposits that aggregate, or clump together. Peptides are chains of amino acids; longer chains form proteins. One type of peptide, called amyloid beta, is found in Alzheimer plaques in neurons of the brain. The other type, amylin, is found in the pancreas and the brain. Two years ago, researchers found both molecules in the pancreas of diabetic patients, and in both diseases their presence has been linked to the progression of the disease state.
To explore the hypothesis that interactions between the two molecules might play a critical role in the self-assembly of peptides that leads to protein aggregation, Yifat Miller, assistant professor from Ben-Gurion University of the Negev, Beer-Sheva, Israel, characterized the way the two protein molecules interact with each other through an examination of their structure. It was the first analysis of its kind.
"By identifying the specific ‘hot regions’ of these peptides that strongly interact with each other, our study may provide insight into the link between type 2 diabetes and Alzheimer’s disease," Miller says. "We believe that preventing these interactions by developing a drug will decrease the risk that type 2 diabetes patients face of developing Alzheimer’s disease later life."
A multi-center study supports the effectiveness of the newest technology available for the treatment of difficult, life-threatening brain aneurysms. The technology, the Pipeline embolization device, is a flow diverter that redirects blood flow away from wide-necked or giant aneurysms that cannot be treated in more conventional ways.
Andrew Ringer, MD, director of the division of cerebrovascular surgery and professor of neurosurgery and radiology at the University of Cincinnati (UC) College of Medicine, led the Cincinnati portion of the study, which was published in the December issue of Neurosurgery.
"The study showed that the Pipeline device is a safe and effective tool for patients and surgeons," says Ringer, a Mayfield Clinic neurosurgeon who has treated 11 patients with the device. "This expands our ability to safely treat aneurysms that were very difficult to treat before."
Excessive alcohol use accounts for 4% of the global burden of disease, and binge drinking particularly is becoming an increasing health issue. A new review article published in Cortex highlights the significant changes in brain function and structure that can be caused by alcohol misuse in young people.
Functional signs of brain damage from alcohol misuse in young people mainly include deficits in visual learning and memory as well as executive functions. These functions are controlled by the hippocampus and frontal structures of the brain, which are not fully mature until around 25 years of age. Structural signs of alcohol misuse in young people include shrinking of the brain and significant changes to white matter tracts.
Age of first use may be considered to trigger alcohol misuse. According to the researchers however, changing the legal drinking age is not the answer. In Australia the legal drinking age is 18, three years earlier than in the US. Despite the difference in legal drinking age, the age of first use (and associated problems) is the same between the two countries.
Instead, the authors stressed the need for early intervention, by identifying markers and thresholds of risky drinking behaviour at an early stage, while individuals are in vulnerable stages of brain development.
Researchers at the University of Glasgow are hoping to help victims of stroke to overcome physical disabilities by helping their brains to ‘rewire’ themselves.
Doctors and scientists from the Institute of Cardiovascular and Medical Sciences will undertake the world’s first in-human trial of vagus nerve stimulation in stroke patients. Stroke can result in the loss of brain tissue and negatively affect various bodily functions from speech to movement, depending on the location of the stroke.
The study, which will be carried out at the Western Infirmary in Glasgow, will recruit 20 patients who suffered a stroke around six months ago and who have been left with poor arm function as a result.
Each participant will receive three one-hour sessions of intensive physiotherapy each week for six weeks to help improve their arm function.
Half of the group will also receive an implanted Vivistim device, a vagus nerve stimulator, which connects to the vagus nerve in the neck. When they are receiving physiotherapy to help improve their arm, the device will stimulate the nerve.
It is hoped that this will stimulate release of the brain’s own chemicals, called neurotransmitters, that will help the brain form new neural connections which might improve participants ability to use their arm.
Lead researcher Dr Jesse Dawson, a Stroke Specialist and Clinical Senior Lecturer in Medicine, said: “When the brain is damaged by stroke, important neural connections that control different parts of the body can be damaged which impairs function.
“Evidence from animal studies suggests that vagus nerve stimulation could cause the release of neurotransmitters which help facilitate neural plasticity and help people re-learn how to use their arms after stroke; particularly if stimulation is paired with specific tasks. A slightly different type of vagus nerve stimulation is already successfully used to manage conditions such as depression and epilepsy.
“This study is designed to provide evidence to support whether this is the case after stroke but our primary aim is to assess feasibility of vagus nerve stimulation after stroke.
“It remains to be seen how much we can improve function, but if we can help people perform even small actions again, like being able to hold a cup of tea, it would greatly improve their quality of life.”
Stem cells from bone marrow or fat improve recovery after stroke in rats, finds a study published in BioMed Central’s open access journal Stem Cell Research & Therapy. Treatment with stem cells improved the amount of brain and nerve repair and the ability of the animals to complete behavioural tasks.
Stem cell therapy holds promise for patients but there are many questions which need to be answered, regarding treatment protocols and which cell types to use. This research attempts to address some of these questions.
Rats were treated intravenously with stem cells or saline 30 minutes after a stroke. At 24 hours after stroke the stem cell treated rats showed a better functional recovery. By two weeks these animals had near normal scores in the tests. This improvement was seen even though the stem cells did not appear to migrate to the damaged area of brain. The treated rats also had higher levels of biomarkers implicated in brain repair including, the growth factor VEGF.
A positive result was seen for both fat (adipose) and bone-marrow derived stem cells. Dr Exuperio Díez-Tejedor from La Paz University Hospital, explained, “Improved recovery was seen regardless of origin of the stem cells, which may increase the usefulness of this treatment in human trials. Adipose-derived cells in particular are abundant and easy to collect without invasive surgery.”
King’s College London has been awarded a six year €15m ‘Synergy grant’ by the European Research Council (ERC) to map the development of nerve connections in the brain before and just after birth.
The Developing Human Connectome Project (dHCP) will use world-leading MR imaging facilities in the Evelina Children’s Hospital Neonatal Unit at St Thomas’ Hospital to help understand how the brain develops, and to see how it is affected by genetic variation or problems like preterm birth. This will provide insights into conditions such as Autistic Spectrum Disorder.
Professor David Edwards, Director of the Centre for the Developing Brain, who is leading the collaboration, said: ‘This is about understanding how the human brain assembles itself. By the time a baby is born, the brain is well developed and key connections between nerves have already been made, so we are looking at babies in the womb. We want to map the nerve connections that form as the brain grows and develops.’
The resulting map will be made freely available to the research community to help improve understand and develop treatments for neurological disorders.
The ground-breaking collaboration brings together world-leaders in medicine, engineering, computer science, and physics from King’s College London, Imperial College London, and the University of Oxford.
Epilepsy is one of the most common neurological conditions worldwide, and it is well known that it is significantly more prevalent in poorer countries and rural areas. The study of more than half a million people in five countries of sub-Saharan Africa is the first to reveal the true extent of the problem and the impact of different risk factors.
The study - conducted at International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH) demographic surveillance sites in Kenya, South Africa, Uganda, Tanzania and Ghana - screened 586 607 residents and identified 1711 who were diagnosed as having active convulsive epilepsy.
These individuals, along with 2033 who did not have epilepsy, were given a questionnaire to complete about their lifestyle habits. The team also took blood samples to test for exposure to malaria, HIV and four other parasitic diseases that are common in low-income countries.
The team found that adults who had been exposed to parasitic diseases were 1.5 to 3 times more likely to have epilepsy than those who had not. Epilepsy has previously been linked with various parasite infections, but this is the first study to reveal the extent of the problem.
Professor Charles Newton from the Wellcome Trust programme at the Kenyan Medical Research Institute (KEMRI) and the Department of Psychiatry at Oxford University, who led the study, said: “This study demonstrates that many cases of epilepsy could be entirely preventable with elimination of parasites in Africa, some of which - for example, onchocerciasis - have been controlled in some areas. In some areas the incidence of epilepsy could be reduced by 30-60 per cent with appropriate control measures.”
In children, the greatest risk factors for developing epilepsy were complications associated with delivery and head injury. Interventions to improve antenatal and perinatal care could substantially reduce the prevalence of epilepsy in this region, say the authors.
The study focused on people with convulsive epilepsies as they are the most reliably detected and reported and there remains a substantial stigma attached to patients with the disease.
“Facilities for diagnosis, treatment and ongoing management of epilepsy are virtually non-existent in many of the world’s poorest regions, so it’s vital that we take these simple steps to try and prevent as many cases of this debilitating disease as possible,” Professor Newton added.
The findings were published today in the journal ‘Lancet Neurology’. The study was funded by the Wellcome Trust, with support from the University of the Witwatersrand and the South African Medical Research Council.
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Researchers at Boston University School of Medicine (BUSM) led by Carmela Abraham, PhD, professor of biochemistry, along with Cidi Chen, PhD, and other collaborators, report that the protein Klotho plays an important role in the health of myelin, the insulating material allowing for the rapid communication between nerve cells. These findings, which appear online in Journal of Neuroscience, may lead to new therapies for multiple sclerosis (MS) and Alzheimer’s disease (AD), in which white matter abnormalities are also common but have been largely ignored.
MS is an inflammatory disease which damages the fatty myelin sheaths around the axons of the brain and spinal cord. This destruction, loss or scarring of the sheaths results in a broad spectrum of symptoms. Disease onset usually occurs in young adults, most commonly women.
In MS the myelin is attacked by the immune system and may not be completely restored by myelin-producing cells (mature oligodendrocytes). The researchers discovered that the addition of Klotho protein to immature oligodendrocytes causes them to mature and manufacture proteins needed for the production of healthy myelin.
"These results taken together indicate that Klotho could become a drug target for multiple sclerosis and other white matter diseases, including AD," explained Abraham.
Abraham and her colleagues have identified, and are working on optimizing, a number of small molecules that could form the basis for the development of therapeutic drugs, which would increase the amount of Klotho protein in the brain.
Since Klotho is not only an age suppressor but also a tumor suppressor, as shown by other research groups, interventions with Klotho-enhancing drugs may solve some of the most treatment-resistant human ailments according to Abraham.
Klotho was named after the Greek Goddess and daughter of Zeus, who spins the thread of life. Abraham’s lab was the first to publish (in 2008) that Klotho levels in the brain decrease with age.
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Testosterone and its derivatives could constitute an efficient treatment against myelin diseases such as multiple sclerosis, reveals a study by researchers from the Laboratoire d’Imagerie et de Neurosciences Cognitives (CNRS/Université de Strasbourg), in collaboration in particular with the “Neuroprotection et Neurorégénération: Molécules Neuroactives de Petite Taille” unit (Inserm/Université Paris-Sud). Myelin composes the sheaths that protect the nerve fibers and allow the speed of nerve impulses to be increased. A deficit in the production of myelin or its destruction cause serious illnesses for which there is no curative treatment. The researchers have shown that in mice brains whose nerve fibers have been demyelinated, testosterone and a synthetic analog induce the regeneration of oligodendrocytes, the cells responsible for myelination, and that they stimulate remyelination. This work is published on January in the journal Brain.
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Scientists have found an early step in how the brain’s inhibitory cells get excited. A natural balance of excitement and inhibition keeps the brain from firing electrical impulses randomly and excessively, resulting in problems such as schizophrenia and seizures. However excitement is required to put on the brakes.
“When the inhibitory neuron is excited, its job is to suppress whatever activity it touches,” said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics at the Medical College of Georgia at Georgia Regents University and corresponding author of the study in Nature Neuroscience.
Mei and his colleagues found that the protein erbin, crucial to brain development, is critical to the excitement.