Category Archives: Research News (General)

A study of the brains of mice shows that structural deterioration associated with old age can be prevented by long-term aerobic exercise starting in mid-life, according to a research article published in PLOS Biology. Researchers found that structural changes that make the blood-brain barrier leaky and result in inflammation of brain tissues in old mice can be mitigated by allowing the animals to run regularly, so providing a potential explanation for the beneficial effects of exercise on dementia in humans.

Physical activity is already known to ameliorate the cognitive decline and sensorimotor deficits seen in old age in humans as well as in mice. To investigate the impact of long-term physical exercise on the brain changes seen in the aging mice, the researchers provided the animals with a running wheel from 12 months old (equivalent to middle aged in humans) and assessed their brains at 18 months (equivalent to ~60yrs old in humans, when the risk of Alzheimer’s disease is greatly increased). Young and old mice alike ran about two miles per night, and this physical activity improved the ability and motivation of the old mice to engage in the typical spontaneous behaviors that seem to be affected by aging. This exercise significantly reduced age-related pericyte loss in the brain cortex and improved other indicators of dysfunction of the vascular system and blood-brain barrier.

Source: PLOS Biology

Investigators have discovered a mechanism behind the spread of neurofibrillary tangles – one of the two hallmarks of Alzheimer’s disease – through the brains of affected individuals. In a report in the journal Nature Communications, researchers describe finding that a particular version of the tau protein, while extremely rare even in the brains of patients with Alzheimer’s disease, is able to spread from one neuron to another and how that process occurs.

“It has been postulated that tangles – the abnormal accumulation of tau protein that fills neurons in Alzheimer’s disease – can travel from neuron to neuron as the disease progresses, spreading dysfunction through the brain as the disease progresses. But how that happens has been uncertain,” said Bradley Hyman, M.D., Ph.D., director of the Massachusetts General Hospital (MGH) Alzheimer’s Disease Research Center and senior author of the report. “Our current study suggests one mechanism at play is that a unique and rare type of tau has the properties we were looking for – it is released from neurons, taken up by other neurons, transported up and down axons, and then released again.”

The current study revealed that, when brain samples from that mouse model were applied to cultured neurons, only 1 percent of the tau in those samples was taken up by the neurons. The tau proteins that were taken up were high molecular weight – meaning that a number of smaller proteins are bound together into a larger molecule – soluble, and studded with a large number of phosphate molecules, a known characteristic of the tau in Alzheimer’s-associated tangles. Similar results were seen in experiments using brain samples from Alzheimer’s patients, both in cultured neurons and in living mice.

Source: Massachusetts General Hospital

New research could lead to improved methods of detection for early-onset Parkinson’s disease (PD).

Recording the responses of fruit flies (Drosophila melanogaster) to different visual patterns, using methods adapted from the study of vision in humans, scientists investigated the nervous systems of flies with different types of Parkinson’s mutations.

The researchers compared flies carrying mutations associated with early-onset Parkinson’s with ‘normal’ control flies and found increased neuronal activity to stimulation in the former group in ‘young’ flies.

By mapping the visual responses of fruit flies with different Parkinson’s genes, the scientists built a substantial data bank of results. Using this they were able to classify unknown flies as having a Parkinson’s-related mutation with 85 per cent accuracy.

Researchers believe it may be possible to transfer this method back to the clinic where early changes in vision may provide a ‘biomarker’ allowing screening for Parkinson’s before the onset of traditional motor-symptoms. Therefore, profiling human visual responses could prove an accurate and reliable test in diagnosing people with early-onset PD.

This method is also likely to succeed when transferred to human detection of Parkinson’s, as visual profiling in humans has proved accurate in the past in detecting genetic markers. In this study, as more complex light stimulations have been used, a more accurate picture of detecting a wider variety of different genetic markers has been revealed.

Source: University of York

Alzheimer’s disease is characterised by two types of lesions, amyloid plaques and degenerated tau protein. Cholesterol plays an important role in the physiopathology of this disease. Two research teams have shown, in a rodent model, that overexpressing an enzyme that can eliminate excess cholesterol from the brain may have a beneficial action on the tau component of the disease, and completely correct it. This is the first time that a direct relationship has been shown between the tau component of Alzheimer’s disease and cholesterol. This work is published in Human Molecular Genetics.

The first step in this work made it possible to show that injecting a viral vector, AAV-CYP46A1, effectively corrects a mouse model of amyloid pathology of the disease, the APP23 mouse. CYP46A1 thus appears to be a therapeutic target for Alzheimer’s disease.

Conversely, in vivo inhibition of CYP46A1 in the mice, using antisense RNA molecules delivered by an AAV vector administered to the hippocampus, induces an increase in the production of Aß peptides, abnormal tau protein, neuronal death and hippocampal atrophy, leading to memory problems. Together these elements reproduce a phenotype mimicking Alzheimer’s disease.

These results demonstrate the key role of cholesterol in the disease, and confirm the relevance of CYP46A1 as a potential therapeutic target (work published in Brain on 3 July 2015).

Taken together, this work now enables the research team to propose a gene therapy approach for Alzheimer’s disease: intracerebral administration of a vector, AAV-CYP46A1, in patients with early and severe forms (1% of patients, familial forms) for whom there is no available treatment.

Source: Inserm

Researchers have made a new discovery about Huntington’s disease, showing that the gene that causes the fatal disorder makes an unexpected “cocktail” of mutant proteins that accumulate in the brain.

The findings are significant because these newly identified mutant proteins kill neurons and build up in regions of the brain that are most affected by the disease. The findings were published in the journal Neuron.

The researchers examined the brains of 12 deceased adult and juvenile patients with Huntington’s disease. They found novel proteins that were abundant in areas of patients’ brains that showed cell death, neuronal loss and other signs of disease, including neuroinflammation.

Along with a protein already implicated in Huntington’s disease, the researchers found four proteins that also contribute to the disease pathology. The disease stems from a genetic mutation in the Huntingtin gene that produces too many copies of a DNA segment known as CAG, which gives rise to a longer Huntingtin protein with toxic effects. However, researchers found that this DNA repeat mutation can undergo a process known as repeat associated non-ATG (RAN) translation, producing four additional damaging repeat proteins that accumulate in the brain. This was a surprise to the researchers because these RAN proteins are made without a signal in the genetic code that was previously thought to be required for protein production. Each of the four RAN proteins contains long repeats of certain single protein building blocks, or amino acids.

Finding these novel RAN proteins in degenerated areas of the brain that were negative for the previously known mutant Huntingtin protein was crucial to linking them to the disease, said Monica Bañez-Coronel, Ph.D., a postdoctoral associate and the first author of the journal article.

Source: University of Florida

Alzheimer’s patients frequently suffer from sleep disorders, mostly even before they become forgetful, and it is known that sleep plays a very important role in memory formation. Researchers have now been able to show for the first time how the pathological changes in the brain act on the information-storing processes during sleep. Using animal models, they were able to decode the exact mechanism and alleviate the impairment with medicinal agents. The study was published in Nature Neuroscience.

The sleep slow waves, also known as slow oscillations, which our brain generates at night, have a particular role in consolidating what we have learned and in shifting memories into long-term storage. These waves are formed via a network of nerve cells in the brain’s cortex, and then spread out into other parts of the brain, such as the hippocampus.

The study used mouse models, which form the same protein deposits, known as β-amyloid plaques, that are visible in human patients. The scientists were able to show that these plaques directly impair the slow wave activity. The scientists also succeeded in decoding this defect at the molecular level: correct spread of the waves requires a precise balance to be maintained between the excitation and inhibition of nerve cells. In the Alzheimer models, this balance was disturbed by the protein deposits, so that inhibition was reduced.

The researchers used this knowledge to treat the defect with medication. One group of sleep-inducing drugs, benzodiazepines, is known to boost inhibitory influences in the brain. If the scientists gave small amounts of this sleep medication to the mice (approximately one-tenth of the standard dose), the sleep slow waves were able to spread out correctly again. In subsequent behavioral experiments, they were able to demonstrate that learning performance had improved as well.

Source: Technical University of Munich

JPND Board Member Dr. John Hardy of the UCL Institute of Neurology was awarded the $3 million Breakthrough Prize in Life Sciences for his pioneering research into the genetic causes of Alzheimer’s disease, other forms of dementia and Parkinson’s disease.

The Breakthrough Prize in Life Sciences honours ‘transformative advances toward understanding living systems and extending human life’. This is the first time that the prize has been awarded to a UK researcher.

Using innovative genetic analysis methods, Professor Hardy has made major contributions to the study of almost all major neurodegenerative diseases. He has published over 850 scientific papers, many of which are focused on neurological disorders and more specifically the genetics of Alzheimer’s disease. His research has underpinned nearly all basic science and treatment research into Alzheimer’s disease over the last 20 years.

“It is a great honour to be awarded the prize for our work dissecting the causes of Alzheimer and Parkinson’s diseases,” Hardy said. “It is, of course, our hope and aim that this understanding leads to effective treatments…I feel we can beat these diseases.”

Source: UCL

The Alzheimer’s Association International Conference® (AAIC) is the world’s largest forum for the dementia research community. the 2015 conference takes place in Washington DC between July 18-23rd.

International investigators, clinicians and care providers gather annually to share the latest study results, theories and discoveries to bring the world closer to breakthroughs in dementia science.

As part of the Alzheimer’s Association’s research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

The programme for this year’s meeting is available at the link below.

Research has uncovered further evidence of a system in the brain that persistently maintains memories for long periods of time. And paradoxically, it works in the same way as mechanisms that cause mad cow disease and other degenerative brain diseases.

In four papers published in Neuron and Cell Reports, researchers show how prion-like proteins – similar to the prions behind mad cow disease in cattle and Creutzfeld-Jakob disease in humans – are critical for maintaining long-term memories in mice, and probably in other mammals. The lead authors of the four papers are Luana Fioriti, Joseph Stephan, Luca Colnaghi and Bettina Drisaldi.

When long-term memories are created in the brain, new connections are made between neurons to store the memory. But those physical connections must be maintained for a memory to persist, or else they will disintegrate and the memory will disappear within days.Many researchers have searched for molecules that maintain long-term memory, but their identity has remained elusive.These memory molecules are a normal version of prion proteins, according to new research.

In one of many experiments described in the paper by Luana Fioriti, the researchers challenged mice to repeatedly navigate a maze, allowing the animals to create a long-term memory. But when the researchers knocked out the animal’s CPEB3 gene two weeks after the memory was made, the memory disappeared.

The researchers then discovered how CPEB3 works inside the neurons to maintain long-term memories. “Like disease-causing prions, functional prions come in two varieties, a soluble form and a form that creates aggregates,” said. Kandel. “When we learn something and form long-term memories, new synaptic connections are made, the soluble prions in those synapses are converted into aggregated prions. The aggregated prions turn on protein synthesis necessary to maintain the memory.”

As long as these aggregates are present, Kandel says, long-term memories persist. Prion aggregates renew themselves by continually recruiting newly made soluble prions into the aggregates. “This ongoing maintenance is crucial,” said Dr. Kandel. “It’s how you remember, for example, your first love for the rest of your life.”

A similar protein exists in humans, suggesting that the same mechanism is at work in the human brain, but more research is needed. “It’s possible that it has the same role in memory, but until this has been examined, we won’t know,” said Dr. Kandel. “There are probably other regulatory components involved,” he added. “Long-term memory is a complicated process, so I doubt this is the only important factor.

Source: Medical News Net

Beyond the four-letter alphabet of the genome, a far richer code dictates when and where genes are transcribed. The epigenome—defined by an ever-expanding list of modifications to DNA and the proteins that interact with it—determines which genes are dialed up or down and gives each cell type its unique personality. Thickening an already dense plot, three recent papers suggest that the brain may have its own epigenetic lingo.

One, published in Neuron on June 17, described the epigenome of three different types of neuron from the mouse brain—one excitatory, and two inhibitory. Among a slew of other findings, the study reported that neurons harbor a striking degree of cytosine methylation beyond the well-known cytosine-guanine (CpG) sites. This novel modification more closely correlated with gene expression and with neuronal phenotype than did the more common CpG methylation.

To generate a more detailed epigenetic map of neurons in the mouse brain, the researchers employed a technique called INTACT (isolation of nuclei tagged in specific cell types) to study nuclei from three types of neuron (see image above). The technique, which uses antibodies to capture nuclei expressing a protein tag, had been established in a plant model, and later used in flies, worms, and frogs, but never in mammals. INTACT isolates nuclei from homogenized tissue that is first frozen intact. This eliminates the need to first separate or sort the different types of cells, which can damage and/or activate neurons and confound results. INTACT allows researchers to obtain enough genetic material from specific cell types to run methylation and other epigenetic analyses.

Source: AlzResearch Forum