Tag Archives: neurodegeneration

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

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

Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons and with mitochondrial dysfunction.

Autophagy is a powerful process for removing such proteins and for maintaining mitochondrial homeostasis. Over recent years, evidence has accumulated to demonstrate that upregulation of autophagy may protect against neurodegeneration.However, autophagy dysfunction has also been implicated in the pathogenesis of various diseases.

This Review summarizes the progress that has been made in our understanding of how perturbations in autophagy are linked with neurodegenerative diseases and the potential therapeutic strategies resulting from the modulation of this process.

Three former top researchers at Genentech (now part of Roche Holding), have raised $217 million in venture capital to start a new company, Denali Therapeutics, focused on treating and curing neurodegenerative diseases like Alzheimer’s, ALS, and Parkinson’s.

The news is sign of a financial turnaround for research efforts against these brain diseases that have been tough to beat.

NeuroPerspective, a newsletter that tracks neurological treatments, says in the past five years the number of drugs being developed by large drug makers for brain and nervous system disorders fell 50% to 129 – but that last year, investors poured $3.3 billion into the field, more than in any of the last ten years.

The raise for Denali is a series A, the very first round of getting funding for a new company. It is the largest such round in biotech history.

Three leading research funders from the UK and North America have joined forces to launch a new global initiative called MEND or, MEchanisms of cellular death in NeuroDegeneration, with a fund of $1.25 million USD for targeted research into brain diseases that cause dementia, such as Alzheimer’s.

Alzheimer’s Research UK, the Alzheimer’s Association based in the U.S. and the Weston Brain Institute in Canada, whose participation in MEND is funded by Selfridges, announce the collaboration in response to the G7 health leaders’ commitment to collectively and significantly increase funding for dementia research, as announced at their December 2013 summit. G7 health leaders met in Bethesda, Maryland (U.S.A), last week to review progress on their goal to identify a cure or disease-modifying treatment by 2025.

MEND is open to applications from scientists around the globe, and researchers will be encouraged to collaborate on projects, sharing knowledge and resources in order to speed up progress. It’s hoped the scheme will also help answer fundamental questions about the similarities and differences between different diseases, such as whether the underlying mechanisms that cause cell death differ from one disease to another, and why each disease affects different types.

Source: Medical News.net