Posts tagged neurodegenerative diseases

People with degenerative neurological conditions could benefit from research that shows why their brain cells stop communicating properly.

Scientists believe that the findings could help to develop treatments that slow the progress of a broad range of brain disorders such as Huntington’s, Alzheimer’s and Parkinson’s diseases.

The team at the University, led by Professor Tom Gillingwater, analysed how connection points between brain cells break down during disease and identified six proteins that control the process.

Sending Signals

When connection points in the brain, known as synapses, stop working - because of injury or disease - the chain of brain signalling breaks down and cannot be repaired.

The research from The Roslin Institute and Centre for Integrative Physiology at the University will help scientists identify drugs that target these proteins.

This could eventually enable clinicians to slow the progress of these disorders.

This study has identified key proteins that may control what goes wrong in a range of brain disorders. We now hope to identify drugs that prevent the breakdown of communication between brain cells and, as a result, halt the progress of these devastating neurodegenerative conditions. — Dr Thomas Wishart Career Track Fellow, The Roslin Institute at the University

(Source: ed.ac.uk)

Misfolded proteins can cause various neurodegenerative diseases such as spinocerebellar ataxias (SCAs) or Huntington’s disease, which are characterized by a progressive loss of neurons in the brain. Researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany, together with their colleagues of the Université Paris Diderot, Paris, France, have now identified 21 proteins that specifically bind to a protein called ataxin-1. Twelve of these proteins enhance the misfolding of ataxin-1 and thus promote the formation of harmful protein aggregate structures, whereas nine of them prevent the misfolding (PLoS Genetics).

Proteins only function properly when the chains of amino acids, from which they are built, fold correctly. Misfolded proteins can be toxic for the cells and assemble into insoluble aggregates together with other proteins. Ataxin-1, the protein that the researchers have now investigated, is very prone to misfolding due to inherited gene defects that cause neurodegenerative diseases. The reason for this is that the amino acid glutamine is repeated in the amino acid chain of ataxin-1 very often - the more glutamine, the more toxic the protein. Approximately 40 repeats of glutamine are considered to be toxic for the cells.

Now, Dr. Spyros Petrakis, Dr. Miguel Andrade, Professor Erich Wanker and colleagues have identified 21 proteins that mainly interact with ataxin-1 and influence its folding or misfolding. Twelve of these proteins enhance the toxicity of ataxin-1 for the nerve cells, whereas nine of the identified proteins reduce its toxicity.

Furthermore, the researchers detected a common feature in the structure of those proteins that enhances toxicity and aggregation. It is a special structure scientists call “coiled-coil-domain” because it resembles a double twisted spiral or helix. Apparently this structure promotes aggregation, because proteins that interact with ataxin-1 and have this domain enhance the toxic effect of mutated ataxin-1. As the researchers said, this structure could be a potential target for therapy: “A careful analysis of the molecular details could help to discover drugs that suppress toxic processes.”

(Source: mdc-berlin.de)

Scientists at Washington University School of Medicine in St. Louis have taken one of the first detailed looks into how Alzheimer’s disease disrupts coordination among several of the brain’s networks. The results, reported in The Journal of Neuroscience, include some of the earliest assessments of Alzheimer’s effects on networks that are active when the brain is at rest.

“Until now, most research into Alzheimer’s effects on brain networks has either focused on the networks that become active during a mental task, or the default mode network, the primary network that activates when a person is daydreaming or letting the mind wander,” says senior author Beau Ances, MD, assistant professor of neurology. “There are, however, a number of additional networks besides the default mode network that become active when the brain is idling and could tell us important things about Alzheimer’s effects.”

Ances and his colleagues analyzed brain scans of 559 subjects. Some of these subjects were cognitively normal, while others were in the early stages of very mild to mild Alzheimer’s disease. Scientists found that all of the networks they studied eventually became impaired during the initial stages of Alzheimer’s.

“Communications within and between networks are disrupted, but it doesn’t happen all at once,” Ances says. “There’s even one network that has a momentary surge of improved connections before it starts dropping again. That’s the salience network, which helps you determine what in your environment you need to pay attention to.”

Other networks studied by the researchers included:

• the dorsal attention network, which directs attention toward things in the environment that are salient;

• the control network, believed to be active in consciousness and decision-making; and

• the sensory-motor network, which integrates the brain’s control of body movements with sensory feedback (e.g., did the finger that just moved strike the right piano key?).

Scientists also examined Alzheimer’s effects on a brain networking property known as anti-correlations. Researchers identify networks by determining which brain areas frequently become active at the same time, but anti-correlated networks are noteworthy for the way their activities fluctuate: when one network is active, the other network is quiet. This ability to switch back-and-forth between networks is significantly diminished in participants with mild to moderate Alzheimer’s disease.

The default mode network, previously identified as one of the first networks to be impaired by Alzheimer’s, is a partner in two of the three pairs of anti-correlated networks scientist studied.

“While we can’t prove this yet, one hypothesis is that as things go wrong in the processing of information in the default mode network, that mishandled data is passed on to other networks, where it creates additional problems,” Ances says.

It’s not practical to use these network breakdowns to clinically diagnose Alzheimer’s disease, Ances notes, but they may help track the development of the disease and aid efforts to better understand its spread through the brain.

Ances plans to look at other markers for Alzheimer’s disease in the same subjects, such as levels in the cerebrospinal fluid of amyloid beta, a major component of Alzheimer’s plaques.

(Source: news.wustl.edu)

People who bear the genetic mutation for Huntington’s disease learn faster than healthy people. The more pronounced the mutation was, the more quickly they learned. This is reported by researchers from the Ruhr-Universität Bochum and from Dortmund in the journal Current Biology. The team has thus demonstrated for the first time that neurodegenerative diseases can go hand in hand with increased learning efficiency. “It is possible that the same mechanisms that lead to the degenerative changes in the central nervous system also cause the considerably better learning efficiency” says Dr. Christian Beste, head of the Emmy Noether Junior Research Group “Neuronal Mechanisms of Action Control” at the RUB.

Passive learning through repeated stimulus presentation

In a previous study, the Bochum psychologists reported that the human sense of vision can be changed in the long term by repeatedly exposing subjects to certain visual stimuli for short periods (we reported in May 2011). The task of the participants was to detect changes in the brightness of stimuli. They performed better if they had viewed the stimuli passively for a while first. In the current study, the researchers presented the same task to 29 subjects with the genetic mutation for Huntington’s disease, who, however, did not yet show any symptoms. They also tested 45 control subjects without such mutations in the genome. In both groups, the learning efficiency was better after passive stimulus presentation than without the passive training. Subjects with the Huntington’s mutation, however, increased their performance twice as fast as those without the mutation.

Glutamate may have paradoxical effect

Degenerative diseases of the nervous system are based on complex changes. A key mechanism is an increased release of the neurotransmitter glutamate. However, since glutamate is also important for learning, in some cases it could lead to the paradoxical effect: better learning efficiency despite degeneration of the nerve cells.

Detecting differences in brightness under aggravated conditions

In each experimental run, the subjects saw two consecutive small bars on a computer screen that either had the same or different brightness. Sometimes, however, not only the brightness changed from bar one to bar two, but also the orientation of the bar (vertical or horizontal). “Normally, the distraction stimulus, i.e. the change in orientation, draws all the attention” Christian Beste explains. “But after the passive training with the visual stimuli, the distraction stimulus has no effect at all.” The shift of attention from the non-relevant to the relevant properties of the stimulus was also visible in the electroencephalogram (EEG) in brain areas for early visual processing.

Better performance with stronger mutation

In Huntington’s disease, a short segment of a gene is repeated. The number of repetitions determines when the disease breaks out. In the present study, a greater number of repetitions was, however, also associated with higher learning efficiency. “This shows that neurodegenerative changes can cause paradoxical effects” says Christian Beste. “The everyday view that neurodegenerative changes fundamentally entail deterioration of various functions can no longer be maintained in this dogmatic form.”

(Source: aktuell.ruhr-uni-bochum.de)

The research, published in Aging Cell, opens up new avenues of understanding for conditions where the ageing of neurons are known to be responsible, such as dementia and Parkinson’s disease.

The ageing process has its roots deep within the cells and molecules that make up our bodies. Experts have previously identified the molecular pathway that react to cell damage and stems the cell’s ability to divide, known as cell senescence.

However, in cells that do not have this ability to divide, such as neurons in the brain and elsewhere, little was understood of the ageing process. Now a team of scientists at Newcastle University, led by Professor Thomas von Zglinicki have shown that these cells follow the same pathway.

This challenges previous assumptions on cell senescence and opens new areas to explore in terms of treatments for conditions such as dementia, motor neuron disease or age-related hearing loss.

Newcastle University’s Professor Thomas von Zglinicki who led the research said: “We want to continue our work looking at the pathways in human brains as this study provides us with a new concept as to how damage can spread from the first affected area to the whole brain.”

Working with the University’s special colony of aged mice, the scientists have discovered that ageing in neurons follows exactly the same rules as in senescing fibroblasts, the cells which divide in the skin to repair wounds.

DNA damage responses essentially re-program senescent fibroblasts to produce and secrete a host of dangerous substances including oxygen free radicals or reactive oxygen species (ROS) and pro-inflammatory signalling molecules. This makes senescent cells the ‘rotten apple in a basket’ that can damage and spoil the intact cells in their neighbourhood.  However, so far it was always thought that ageing in cells that can’t divide - post-mitotic, non-proliferating cells - like neurons would follow a completely different pathway.

Now, this research explains that in fact ageing in neurons follows exactly the same rules as in senescing fibroblasts.

Professor von Zglinicki, professor of Cellular Gerontology at Newcastle University said: “We will now need to find out whether the same mechanisms we detected in mouse brains are also associated with brain ageing and cognitive loss in humans. We might have opened up a short-cut towards understanding brain ageing, should that be the case.”

Dr Diana Jurk, who did most of this work during her PhD in the von Zglinicki group, said: “It was absolutely fascinating to see how ageing processes that we always thought of as completely separate turned out to be identical.  Suddenly so much disparate knowledge came together and made sense.”

(Source: ncl.ac.uk)

Executive function tests key to early detection of Alzheimer’s, Concordia study shows

By the time older adults are diagnosed with Alzheimer’s disease, the brain damage is irreparable. For now, modern medicine is able to slow the progression of the disease but is incapable of reversing it. What if there was a way to detect if someone is on the path to Alzheimer’s before substantial and non-reversible brain damage sets in?

This was the question Erin K. Johns, a doctoral student in Concordia University’s Department of Psychology and member of the Center for Research in Human Development (CRDH), asked when she started her research on older adults with mild cognitive impairment (MCI). These adults show slight impairments in memory, as well as in “executive functions” like attention, planning, and problem solving. While the impairments are mild, adults with MCI have a high risk of developing Alzheimer’s disease.

“We wanted to help provide more reliable tools to identify people who are at increased risk for developing Alzheimer’s so that they can be targeted for preventive strategies that would stop brain damage from progressing,” says Johns.

The new study was published in the Journal of the International Neuropsychological Society and was funded by the Quebec Network for Research on Aging and the Canadian Institutes of Health Research. In it, Johns and her colleagues found that people with MCI are impaired in several aspects of executive functioning, the biggest being inhibitory control. 

This ability is crucial for self-control: everything from resisting buying a candy bar at the checkout aisle to resisting the urge to mention the obvious weight gain in a relative you haven’t seen in a while. Adults with MCI also had trouble with tests that measure the ability to plan and organize.

Johns and her colleagues found that all the adults with MCI they tested were impaired in at least one executive function and almost half performed poorly in all the executive function tests. This is in sharp contrast with standard screening tests and clinical interviews, which detected impairments in only 15 percent of those with MCI.

“The problem is that patients and their families have difficulty reporting executive functioning problems to their physician, because they may not have a good understanding of what these problems look like in their everyday life.” says Johns. “That’s why neuropsychological testing is important.”

Executive function deficits affect a person’s everyday life and their ability to plan and organize their activities. Even something as easy as running errands and figuring out whether to go to the drycleaners or to the supermarket can be difficult for adults with MCI. Detecting these problems early could improve patient care and treatment planning.

“If we miss the deficits, we miss out on an opportunity to intervene with the patient and the family to help them know what to expect and how to cope,” says Johns. She is now conducting a follow-up study funded by the Alzheimer Society of Canada and Canadian Institutes of Health Research, along with her supervisor, Natalie Phillips, associate professor in the Department of Psychology and member of CRDH.

Johns hopes her continued research will lead to a better understanding of why these deficits start at such an early stage of Alzheimer’s and what other tools could be used for earlier detection of the disease.

(Source: concordia.ca)