Tag Archives: Research

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.

A new study has found that a healthy diet, regular physical activity and a normal body mass index can reduce the incidence of protein build-ups that are associated with the onset of Alzheimer’s disease.

In the study, 44 adults ranging in age from 40 to 85 (mean age: 62.6) with mild memory changes but no dementia underwent an experimental type of PET scan to measure the level of plaque and tangles in the brain. Researchers also collected information on participants’ body mass index, levels of physical activity, diet and other lifestyle factors. Plaque, deposits of a toxic protein called beta-amyloid in the spaces between nerve cells in the brain; and tangles, knotted threads of the tau protein found within brain cells, are considered the key indicators of Alzheimer’s.

The study, published in the American Journal of Geriatric Psychiatry, found that each one of several lifestyle factors — a healthy body mass index, physical activity and a Mediterranean diet — were linked to lower levels of plaques and tangles on the brain scans. (The Mediterranean diet is rich in fruits, vegetables, legumes, cereals and fish and low in meat and dairy, and characterized by a high ratio of monounsaturated to saturated fats, and mild to moderate alcohol consumption.)

Earlier studies have linked a healthy lifestyle to delays in the onset of Alzheimer’s. However, the new study is the first to demonstrate how lifestyle factors directly influence abnormal proteins in people with subtle memory loss who have not yet been diagnosed with dementia. Healthy lifestyle factors also have been shown to be related to reduced shrinking of the brain and lower rates of atrophy in people with Alzheimer’s.

The next step in the research will be to combine imaging with intervention studies of diet, exercise and other modifiable lifestyle factors, such as stress and cognitive health.

Reprinted from materials provided by UCLA.

For decades, scientists have known that people with two copies of a gene called apolipoprotein E4 (ApoE4) are much more likely to have Alzheimer’s disease at age 65 than the rest of the population. Now, researchers have identified a connection between ApoE4 and protein build-up associated with Alzheimer’s that provides a possible biochemical explanation for how extra ApoE4 causes the disease.

Their findings, which appear in the Journal of the American Chemical Society, underscore the importance of looking at genes and proteins not classically associated with Alzheimer’s to make progress in understanding the disease.

Late-onset Alzheimer’s disease — the subset of the disorder occurring in people age 65 and over — affects more than 5 million Americans, and is characterized by progressive memory loss and dementia. Scientists have put forth a variety of hypotheses on its causes, including the accumulation of protein clusters called beta-amyloid plaques and tau tangles in the brain.

Apolipoprotein E comes in three versions, or variants, called ApoE2, ApoE3 and ApoE4. All the ApoE proteins have the same normal function: carrying fats, cholesterols and vitamins throughout the body, including into the brain. While ApoE2 is protective and ApoE3 appears to have no effect, a mutation in ApoE4 is a well-established genetic risk factor for late-onset Alzheimer’s disease. Previous reports have suggested that ApoE4 may affect how the brain clears out beta-amyloid, but what was happening at the molecular level wasn’t clear.

Scientists had previously uncovered hints that ApoE4 might degrade differently than the other variants, but the protein that carried out this breakdown of ApoE4 was unknown.

To find the protein responsible for degrading ApoE4, the researchers screened tissues for potential suspects and homed in on one enzyme called high-temperature requirement serine peptidase A1 (HtrA1).

When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells — and more of the breakdown products of the protein.

But it’s not just a lack of full-length ApoE or an increase in its fragments that may be causing Alzheimer’s in people with ApoE4. The researchers also found that ApoE4 — because it binds so well to HtrA1 — keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer’s.

The results need be tested and confirmed in animal studies before researchers can be sure that HtrA1 is the link between ApoE4 and Alzheimer’s in humans. But if they hold true, they could point toward a better understanding of the disease and potential new treatment strategies.

Paper: “HtrA1 Proteolysis of ApoE In Vitro Is Allele Selective”
Reprinted from materials provided by the Salk Institute.

nature“The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6” has been published in Nature. This work was supported in part by JPND through the CureALS project and the REfrAME project, both selected under the 2015 JPco-fuND call.

Synucleinopathies, a group of neurodegenerative diseases including Parkinson’s disease, are characterized by the pathological deposition of aggregates of the misfolded α-synuclein protein into inclusions throughout the central and peripheral nervous system. Intercellular propagation (from one neuron to the next) of α-synuclein aggregates contributes to the progression of the neuropathology, but little was known about the mechanism by which spread occurs.

In this study, scientists used fluorescence microscopy to demonstrate that pathogenic α-synuclein fibrils travel between neurons in culture, inside lysosomal vesicles through tunneling nanotubes (TNTs), a new mechanism of intercellular communication.

After being transferred via TNTs, α-synuclein fibrils are able to recruit and induce aggregation of the soluble α-synuclein protein in the cytosol of cells receiving the fibrils, thus explaining the propagation of the disease. The scientists propose that cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. However, this results in the disease being spread to naive neurons.

This study demonstrates that TNTs play a significant part in the intercellular transfer of α-synuclein fibrils and reveals the specific role of lysosomes in this process. This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies.

These compelling findings, together with previous reports from the same team, point to the general role of TNTs in the propagation of prion-like proteins in neurodegenerative diseases and identify TNTs as a new therapeutic target to combat the progression of these incurable diseases.

 

Paper: “Tunneling nanotubes spread fibrillar α‐synuclein by intercellular trafficking of lysosomes”

Reprinted from materials provided by Institut Pasteur.

A new and versatile imaging technique enables researchers to trace the trajectories of whole nerve cells and provides extensive insights into the structure of neuronal networks.

Lesions caused by traumatic brain damage, stroke and functional decline due to aging processes can disrupt the complex cellular network that constitutes the central nervous system, and lead to chronic pathologies, such as dementia, epilepsy and deleterious metabolic perturbations. But exactly how this happens is unknown. Researchers have now refined a novel imaging technique that allows them to visualize and monitor these structural alterations in neuronal networks. The new findings appear in the journal Nature Methods.

Nerve cells transmit electrical impulses over long distances along fibrous connections called axons, which extend from the cell body where the nucleus resides. Indeed, many neurons in the brainstem possess axons that project as far as the base of the spinal column. Thus damage to these axons can affect the function of parts of the central nervous system that are remote from the actual site of injury. The new imaging method is based on a clearing-and-shrinkage procedure that can render whole organs and organisms transparent, making – for instance – the full length of the rodent spinal cord accessible to optical imaging. Moreover, the technique is applicable down to the level of individual cells, which are labeled with fluorescent protein tags and can be visualized under the microscope by irradiating them with visible light. This enables researchers to map complex neuronal networks in rodents in 3D, a significant step in revealing the enigma behind the human brain.

Because essentially all cell types – including immune cells and tumor cells – can be specifically labeled with the aid of appropriate fluorescent markers or antibodies, the new method can be employed in a broad range of biomedical settings. Furthermore, the images obtained can be archived in a database and made available to other researchers, which should help reduce unnecessary duplication of studies.

Paper: “Shrinkage-mediated imaging of entire organs and organisms using uDISCO”

Reprinted from materials provided by LMU Medical Center.

Nature Reviews NeurologySupportive and symptomatic management of amyotrophic lateral sclerosis has been published in Nature Reviews Neurology. This work was supported in part by JPND through the ALS-CarE project, selected under the 2012 healthcare call.

Neurobiology of Disease“The choroid plexus in health and in disease: Dialogues into and out of the brain” has been published in Neurobiology of Disease. This research was supported in part by JPND through the NeuroGem project, selected under the 2013 cross-disease analysis call, and PROP-AD, selected under the 2015 JPco-fuND call.