Yearly Archives: 2016

Prion diseases are deadly neurodegenerative disorders in humans and animals that are characterized by misfolded forms of prion protein (PrP). Development of effective treatments has been hampered by the lack of good experimental models. In a new study published in The American Journal of Pathology, researchers describe the distinct stages of prion disease in the mouse retina and define an experimental model to specifically test therapeutic approaches.

The study used an experimental mouse model of the prion disease scrapie to determine the temporal relationship between the transport of misfolded prion protein (PrPSc) from the brain to the retina, the accumulation of PrPSc in the retina, the inflammatory response of the surrounding retinal tissue, and the loss of neurons.

It is believed that transmissible spongiform encephalopathy (TSE) progression depends on the spread of misfolded protein from one central nervous system structure to another. The investigators injected mouse-adapted scrapie into the brains of mice and studied the movement of misfolded prion protein from the brain into the retina via the optic nerve for up to 153 days post-inoculation (dpi), when clinical disease becomes apparent.

By studying prion disease in the retina, which is relatively isolated from the brain, researchers were able to determine the time lag between stages of the disease process and were able to sequentially detect seeding of misfolded protein in the retina at 60 dpi, followed by accumulation of PrPSc and activation of retinal glia at 90 days, activation of microglia at 105 dpi, and retinal neuronal death at 120 dpi.

Using this information, it is now possible to evaluate a potential therapy for its ability to interfere with accumulation of protein misfolding, to suppress damaging neuroinflammation, or to prevent death of neurons.

Paper: “Temporal Resolution of Misfolded Prion Protein Transport, Accumulation, Glial Activation, and Neuronal Death in the Retinas of Mice Inoculated with Scrapie”
Reprinted from materials provided by Elsevier.

A research project has shown that an experimental model of Alzheimer’s disease can be successfully treated with a commonly used anti-inflammatory drug.

Nearly everybody will at some point in their lives take non-steroidal anti-inflammatory drugs; mefenamic acid, a common Non-Steroidal Anti Inflammatory Drug (NSAID), is routinely used for period pain.

The findings are published in the journal Nature Communications.

Though this is the first time a drug has been shown to target this inflammatory pathway, highlighting its importance in the disease model, the researchers caution that more research is needed to identify its impact on humans, and the long-term implications of its use.

The research paves the way for human trials, which the team hope to conduct in the future.

In the study, transgenic mice that develop symptoms of Alzheimer’s disease were used. One group of 10 mice was treated with mefenamic acid, and 10 mice were treated in the same way with a placebo.

The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month.

Memory loss was completely reversed back to the levels seen in mice without the disease.

“These promising lab results identify a class of existing drugs that have potential to treat Alzheimer’s disease by blocking a particular part of the immune response,” said Dr. Doug Brown, Director of Research and Development at Alzheimer’s Society.

Paper: “Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models”
Reprinted from materials provided by the University of Manchester.

Aducanumab, an antibody developed by the University of Zurich, has been shown to trigger a meaningful reduction of harmful beta-amyloid plaques in patients with early-stage Alzheimer’s disease. These protein deposits in the brain are a classic sign of Alzheimer’s disease and contribute to the progressive degeneration of brain cells. The researchers furthermore demonstrated in an early-stage clinical study that, after one year of treatment with Aducanumab, cognitive decline could be significantly slowed in antibody-treated patients as opposed to the placebo group.

Although the causes of Alzheimer’s disease are still unknown, it is clear that the disease commences with progressive amyloid deposition in the brains of affected persons between ten and fifteen years before the emergence of initial clinical symptoms such as memory loss. Researchers have now been able to show that Aducanumab, a human monoclonal antibody, selectively binds brain amyloid plaques, thus enabling microglial cells to remove the plaques. A one-year treatment with the antibody, as part of a phase Ib study, resulted in almost complete clearance of the brain amyloid plaques in the study group patients. The results, which were realized by researchers at UZH together with the biotech company “Biogen” and the UZH spin-off “Neurimmune,” have been published in Nature.

Reduction of brain amyloid plaque is dependent on treatment duration and dosage

“The results of this clinical study make us optimistic that we can potentially make a great step forward in treating Alzheimer’s disease,” says Roger M. Nitsch, professor at the Institute for Regenerative Medicine at UZH. “The effect of the antibody is very impressive. And the outcome is dependent on the dosage and length of treatment.” After one year of treatment, practically no beta-amyloid plaques could be detected in the patients who received the highest dose of the antibody.

The antibody was developed with the help of a technology platform from “Neurimmune.” Using blood collected from elderly persons aged up to one hundred and demonstrating no cognitive impairment, the researchers isolated precisely those immune cells whose antibodies are able to identify toxic beta-amyloid plaques but not the amyloid precursor protein that is present throughout the human body and that presumably plays an important role in the growth of nerve cells. The good safety profile of Aducanumab in patients may well be attributed to the antibody’s specific capacity to bond with the abnormally folded beta-amyloid protein fragment as well as the fact that the antibody is of human origin.

Investigational treatment also curbs cognitive decline

165 patients with early-stage Alzheimer’s disease were treated in the phase 1b clinical trial. Although not initially planned as a primary study objective, the good results encouraged researchers to additionally investigate how the treatment affected the symptoms of disease. This was evaluated via standardized questionnaires to assess the cognitive abilities and everyday activities of the patients. “Aducanumab also showed positive effects on clinical symptoms,” is how Nitsch sums up the findings. “While patients in the placebo group exhibited significant cognitive decline, cognitive ability remained distinctly more stable in patients receiving the antibody.”

Some of the trial participants temporarily suffered from amyloid-related imaging abnormality (ARIA), an adverse effect that can be detected via magnetic resonance imaging. In a minority of cases, this was accompanied by temporary mild to moderate headaches. The UZH researchers believe that ARIA is a measurable biological effect of amyloid clearance.

The promising effects of Aducanumab are currently being investigated in two large phase-three clinical studies to further evaluate safety and efficacy. Involving over 300 centers in 20 countries throughout North America, Europe, and Asia, these studies are evaluating the effectiveness and safety of the antibody on a total of 2,700 patients with early-stage Alzheimer’s disease.

Paper: “The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease”
Reprinted from materials provided by the University of Zurich.

 

A protein complex called Polycomb Repressive Complex 2 (PRC2), which plays a critical role in forming specific classes of nerve cells in the brain during development, also plays an important role in the adult brain where it may contribute to Huntington’s disease and other neurodegenerative disorders, according to a study published in the journal Nature Neuroscience.

The study focuses on epigenetics, the study of changes in the action of human genes caused by molecules that regulate when, where, and to what degree our genetic material is activated. Protein complexes have an important role in the biochemical processes that are associated with the expression of genes. Some help to silence genes, whereas others are involved in the activation of genes. The importance of such complexes is emphasized by the fact that mice cannot live if they do not possess PRC2.

In the striatum, the brain region that regulates voluntary movements, the majority of neurons are called medium spiny neurons (MSNs), so-called because of their spiny appearance. MSNs are further characterized by the expression of a specific set of genes that determines their unique identity and function. Once specified, an MSN’s identity needs to be maintained throughout life in order to ensure normal motor function.

PRC2 is an epigenetic gene regulator that represses or silences a given gene’s expression. While previous research has found PRC2 to be critical for normal brain development, the role of this protein complex in maintaining the specialization and function of adult MSNs had remained a mystery.

To study the role of PRC2 in MSN formation and function, the researchers generated a mouse model that lacks the PRC2 complex specifically in neurons in the forebrain. The research team found that neurons in mice that lack PRC2, including mice that lacked PRC2 in MSNs, showed inappropriate reactivation of genes that are usually turned off in these cells, and inhibited the expression of genes that are usually turned on and which are essential to the MSN’s specific function. The data suggests that PRC2 not only governs the process of brain cell development but also that PRC2 helps to maintain MSNs’ identity into the animal’s adult life and plays an active role in determining whether the neuron should live or die.

Closer examination of the altered genes in the striatum of the mice that lacked PRC2 revealed that many of these genes controlled by PRC2 are those known to control the process whereby brain cells self-destruct. Consistent with this finding, the PRC2-lacking mice showed signs of progressive cell death in the striatum and had smaller brain mass then non-mutant mice. In addition, these mice developed a progressive and fatal neurodegenerative disorder reminiscent of Huntington’s disease in humans, suggesting that disruption of PRC2 may contribute to neurodegenerative disorders.

Paper: “Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration”
Reprinted from materials provided by Mount Sinai Hospital.

Neuroscientists peered into the brains of patients with Parkinson’s disease and two similar conditions to see how their neural responses changed over time. The study may provide a new tool for testing experimental medications aimed at alleviating symptoms and slowing the rate at which the diseases damage the brain.

Parkinson’s disease is a neurodegenerative disorder that destroys neurons in the brain that are essential for controlling movement. While many medications exist that lessen the consequences of this neuronal loss, none can prevent the destruction of those cells. Clinical trials for Parkinson’s disease have long relied on observing whether a therapy improves patients’ symptoms, but such studies reveal little about how the treatment affects the underlying progressive neurodegeneration. As a result, while there are treatments that improve symptoms, they become less effective as the neurodegeneration advances. The new study could remedy this issue by providing researchers with measurable targets, called biomarkers, to assess whether a drug slows or even stops the progression of the disease in the brain.

The research team used functional magnetic resonance imaging (fMRI) to measure activity in a set of pre-determined brain areas in healthy controls, individuals with Parkinson’s disease, and patients with two forms of “atypical Parkinsonism” – multiple systems atrophy (MSA) and progressive supranuclear palsy (PSP) – that have symptoms similar to those of Parkinson’s disease. The researchers selected the specific brain regions, which are critical for movement and balance, based on the findings of past studies in people with these three conditions. The participants each underwent two scans spaced a year apart, during which they completed a test that gauged their grip strength.

The healthy controls showed no changes in neural activity after a year, whereas the participants with Parkinson’s showed reductions in the response of two brain regions called the putamen and the primary motor cortex. Previous research had shown reduced activity in the primary motor cortex of Parkinson’s patients, but the new study is the first to suggest that this deficit worsens over time. Activity decreased in MSA patients in the primary motor cortex, the supplementary motor area, and the superior cerebellum, while the individuals with PSP showed a decline in the response of these three areas and the putamen.

The researchers now hope to use their newly discovered biomarkers, in addition to one it had previously identified, to test whether an experimental medication known to improve Parkinson’s symptoms also slows the progression of those brain changes.

Paper: “Functional MRI of disease progression in Parkinson disease and atypical parkinsonian syndromes”

Reprinted from materials provided by NIH/NINDS.