Tag Archives: Dementia

Scientists have uncovered a mechanism in the brain that could account for some of the neural degeneration and memory loss in people with Alzheimer’s disease.

The researchers discovered that a common symptom of Alzheimer’s disease – the accumulation of amyloid plaques along blood vessels – could be disrupting blood flow in the brain. The results were published in the journal Brain.

The team discovered that the blood flow regulation of astrocytes — the most populous cell type in the brain — is disrupted by plaques formed of misfolded amyloid protein around blood vessels. In a healthy brain, amyloid protein fragments are routinely broken down and eliminated.

The presence of amyloid proteins around blood vessels in the brain is a hallmark of Alzheimer’s disease, yet it wasn’t understood if the proteins did any harm. Now, the research team has found that they do.

“We found that amyloid deposits separated astrocytes from the blood vessel wall,” said Stefanie Robel, a research assistant professor at the Virginia Tech Carilion Research Institute and a coauthor of the paper. “We also found that these amyloid deposits form an exoskeleton around the blood vessels, a kind of cast that reduces the pliability of the vessels.”

The exoskeleton is known as a vascular amyloid. Its inelasticity might result in lower blood flow, which could account for Alzheimer’s symptoms, such as memory lapses, impaired decision-making, and personality changes.

 

Source: Virginia Tech News

Researchers are proposing a new way of understanding Amyotrophic Lateral Sclerosis (ALS), the devastating and incurable neurological disease. Their findings, published in the journal Neuron, could be a major milestone on the path to a treatment for both ALS and dementia.

By delving into a previously overlooked corner of ALS research, the team discovered a new way in which the disease kills nerve cells.

Many cases of ALS are sparked by a toxic build-up of certain proteins, which cause neurons in the brain and spinal cord to die. Over the last decade, mutations that cause ALS have been found in a growing number of genes that encode RNA-binding proteins. The protein they create commonly builds up inside the diseased brain and spinal cords in ALS patients. Until now, scientists haven’t thought this build-up was important to the disease process because it looked different from the types of protein accumulations — such as tau, amyloid and alpha synuclein — that are clearly toxic and always found in patients with Alzheimer’s, Parkinson’s and some forms of dementia.

The research team decided to take a closer look at these seemingly innocuous protein accumulations. They focused initially on the FUS protein, and discovered that these abnormal clumps could actually be a very important player in causing nerve cell damage and ALS. The research team found that mutations in FUS changed the property of FUS protein so that it tends to form very dense gels that do not easily re-melt and release their cargo appropriately. As a result, it’s unable to deliver the tools necessary for the neurons to stay healthy and do their job.

The next step is for researchers to find ways to prevent the solidification of the gel, or to reverse the hardening process, offering a key to a future drug to treat ALS and frontotemporal dementia — another disease in which the protein is active.

Source: University of Toronto

A new study finds that a component of aspirin binds to an enzyme called GAPDH, which is believed to play a major role in neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases.

Researchers discovered that salicylic acid, the primary breakdown product of aspirin, binds to GAPDH, thereby stopping it from moving into a cell’s nucleus, where it can trigger the cell’s death. The study, which appears in the journal PLOS ONE, also suggests that derivatives of salicylic acid may hold promise for treating multiple neurodegenerative diseases.

The researchers performed high-throughput screens to identify proteins in the human body that bind to salicylic acid. GAPDH, (Glyceraldehyde 3-Phosphate Dehydrogenase), is a central enzyme in glucose metabolism, but plays additional roles in the cell. Under oxidative stress—an excess of free radicals and other reactive compounds—GAPDH is modified and then enters the nucleus of neurons, where it enhances protein turnover, leading to cell death.

The anti-Parkinson’s drug deprenyl blocks GAPDH’s entry into the nucleus and the resulting cell death. The researchers discovered that salicylic acid also is effective at stopping GAPDH from moving into the nucleus and preventing cell death.

“The enzyme GAPDH, long thought to function solely in glucose metabolism, is now known to participate in intracellular signaling,” said co-author Solomon Snyder, professor of neuroscience at Johns Hopkins University in Baltimore. “The new study establishes that GAPDH is a target for salicylate drugs related to aspirin, and hence may be relevant to the therapeutic actions of such drugs.”

Source: Boyce Thompson Institute

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

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

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 EU Joint Programme – Neurodegenerative Disease Research (JPND) will shortly begin another action to support working groups on “Harmonisation and Alignment in Brain Imaging Methods for Neurodegeneration”.

The aim of the call is to establish a limited number of transnational, JPND-sponsored expert working groups to address issues of key relevance for the future use of brain imaging techniques in ND research. Each working group can bid up to €50,000 for support of its activities, which are expected to run for a maximum of 6 months.

This will be a 1-step call, anticipated to launch in early January 2016, with a likely submission deadline of March 2016. Further details will be provided on the call launch date in January 2016. However, any new ideas to tackle harmonisation and alignment in brain imaging will be welcome. For example, this may include:

  • Harmonisation of acquisition for current markers (acquisition and harmonisation of procedures, for example, for MR, FDG PET, and EEG signals)
  • Simplification of web access to image analysis environments (improving the secure access to innovative web-based image analysis environments for neurodegenerative diseases)
  • Innovative PET molecular markers (fostering the use of established and experimental PET methods)
  • Innovative ultra-high field (UHF) MR markers

Please Note:

  • Proposals are not limited to these topics, and may cover other topics within harmonisation and alignment of brain imaging methods.
  • All information regarding future JPND Call topics is subject to change.
  • Final call information will be published on the JPND website (www.jpnd.eu).

The diseases covered by JPND are:
– Alzheimer’s disease (AD) and other dementias
– Parkinson’s disease (PD) and PD‐related disorders
– Prion disease
– Motor neurone diseases (MND)
– Huntington’s Disease (HD)
– Spinocerebellar ataxia (SCA)
– Spinal muscular atrophy (SMA)

 

Over the past few years, the OECD has conducted work in a number of areas related to innovation in biomedical research and health innovation for healthy ageing.

Entitled “Enhancing Translational Research and Clinical Development for Alzheimer’s Disease and other Dementias”, this report is the main output from a Nov 2014 OECD workshop aimed to provide an international forum for all stakeholders to drive forward a change in the global paradigm in biomedical research and health innovation for Alzheimer’s disease and other dementias.

Discussions at the workshop have shown that progress on key issues is being made, thanks to a willingness of stakeholders to join forces and work together towards a future cure.

In line with recommendations of the G8 Dementia Summit Declaration to strengthen collaboration for innovation and cross-sector partnerships this report considers the challenges and options to promote and accelerate research in dementia and its transformation into innovative therapies and diagnostics.