Tag Archives: neurodegeneration

Researchers have shown that the core of the protein clumps found in the brains of people with Huntington’s disease have a distinctive structure, a finding that could shed light on the molecular mechanisms underlying the neurodegenerative disorder. The findings were published in the Proceedings of the National Academy of Sciences.

In Huntington’s and several other progressive brain diseases, certain proteins aggregate to form plaques or deposits in the brain, said senior investigator Patrick C.A. van der Wel, Ph.D., assistant professor of structural biology at Pitt School of Medicine.

“Despite decades of research, the nature of the protein deposition has been unclear, which makes it difficult to design drugs that affect the process,” he said. “Using advanced nuclear magnetic resonance spectroscopy, we were able to provide an unprecedented view of the internal structure of the protein clumps that form in the disease, which we hope will one day lead to new therapies.”

The gene associated with Huntington’s makes a protein that has a repetitive sequence called polyglutamine. In the 1990s, it was discovered that the patients have mutated proteins in which this sequence is too long, yet it has remained unclear how exactly this unusual mutation causes the protein to misbehave, clump together and cause the disease.

“This is exciting because it may suggest new ways to intervene with these disease-causing events,” Dr. van der Wel said. “For the first time, we were able to really look at the protein structure in the core of the deposits formed by the mutant protein that causes Huntington’s. This is an important breakthrough that provides crucial new insights into the process of how the protein undergoes misfolding and aggregation.

He added Huntington’s is one of many neurodegenerative diseases in which unusual protein deposition occurs in the brain, suggesting similar biochemical mechanisms may be involved. Lessons learned in this disease could help foster understanding of how these types of diseases develop, and what role the protein aggregates play.

Source: University of Pittsburgh

A laboratory study indicates that the main protein involved in Parkinson’s disease pathology does not behave as a prion when overexpressed.

In Parkinson’s disease, the protein alpha-synuclein aggregates within neurons of patients and appears to propagate across interconnected areas of the brain. How this happens remains largely unknown. It has been proposed that alpha-synuclein may behave like a prion: pathological forms of the protein may be capable of changing the conformation of normal alpha-synuclein and thus triggering its aggregation and neuron-to-neuron propagation (a phenomenon referred to as “seeding”). Recent findings by scientists reveal that aggregation, spreading and pathology caused by alpha-synuclein do not necessarily involve prion-like seeding. Instead, they could be triggered by enhanced alpha-synuclein expression and trans-neuronal passage of monomeric and oligomeric forms of the protein.

“We believe that these findings bear a number of important implications for disease pathogenesis. Not only can we conclude that long-distance diffusion of alpha-synuclein does not necessarily require the generation of prion-like species,” said researcher Donato Di Monte. “Our data also reveal that spreading and pathology can be triggered by simple overexpression of the protein and are mediated, at least initially, by monomeric and/or oligomeric alpha-synuclein.”

Researchers report on this in the journal Brain.

Source: DZNE

Men taking androgen deprivation therapy (ADT) for prostate cancer were almost twice as likely to be diagnosed with Alzheimer’s disease in the years that followed than those who didn’t undergo the therapy, an analysis of medical records from two large hospital systems has shown. Men with the longest durations of ADT were even more likely to be diagnosed with Alzheimer’s disease.

The findings, published in the Journal of Clinical Oncology, do not prove that ADT increases the risk of Alzheimer’s disease. But the authors say they clearly point to that possibility, and are consistent with other evidence that low levels of testosterone may weaken the aging brain’s resistance to Alzheimer’s.

For the study, researchers evaluated two large sets of medical records, one from the Stanford health system and the other from Mt. Sinai Hospital in New York City. The researchers scanned the records of 1.8 million patients from Stanford Health Care, and, through a prior institutional research agreement, 3.7 million patients from Mount Sinai Hospital.

Among this cohort, they identified about 9,000 prostate cancer patients at each institution, 16,888 of whom had non-metastatic prostate cancer. A total of 2,397 had been treated with androgen deprivation therapy. The researchers compared these ADT patients with a control group of non-ADT prostate cancer patients, matched according to age and other factors.

Using two different methods of statistical analysis, the team showed that the ADT group, compared to the control group, had significantly more Alzheimer’s diagnoses in the years following the initiation of androgen-lowering therapy. By the most sophisticated measure, members of the ADT group were about 88 percent more likely to get Alzheimer’s.

Source: Penn Medicine

The Innovative Medicines Initiative (IMI) has launched a new call for research proposals that will aim to accelerate the development of medicines in a number of key areas, including neurological disorders.

The Alzheimer’s disease and Parkinson’s disease topic of the call focuses on better understanding how the protein tangles found in both diseases spread through the brain, with the ultimate goal of establishing new drug targets.

The IMI initiative, a partnership between the European Union and the pharmaceutical industry association EFPIA, aims to stimulate the development of safer and more effective medicines.

Other topics in the call, known as IMI 2 – Call 7, include safety, pain, cancer, eye diseases, and big data. Call 7 has a budget of €46.8 million from IMI, which will be matched by €46.8 million from the EFPIA companies in the projects. The submission deadline for this call is March 17, 2016.

IMI simultaneously launched a second call, known as IMI 2 – Call 8, for research proposals on Ebola and related diseases.

Visit the IMI website to learn more about the call topics and to apply.

The EU Joint Programme – Neurodegenerative Disease Research (JPND) has announced a rapid-action call inviting leading scientists in the field to bring forward novel approaches that will enhance the use of brain imaging for neurodegenerative disease research.

Imaging techniques such as MR, PET and EEG mapping have brought about a dramatic improvement in the understanding of neurodegenerative diseases such as Alzheimer’s disease. In recent years, access to cutting-edge imaging technologies and platforms has expanded, and advances have been made in the harmonisation of acquisition procedures across scanners and vendors. However, fully capitalising on the use of brain imaging technologies for neurodegeneration research will require the development of new methodologies and the ability to achieve image acquisition and analysis at scale and at the global level.

The aim of the call is to establish a limited number of transnational working groups to address the key challenges facing the use of new and innovative brain imaging techniques in neurodegenerative disease research. The working groups will be community-led and will establish ‘best practice’ guidelines and/or methodological frameworks to overcome these barriers. Each working group can bid up to €50,000 for the support of its activities, which are expected to run for a maximum of 9 months.

According to Professor Philippe Amouyel, Chair of the JPND Management Board:

“JPND recognises that state-of-the-art brain imaging techniques are a vital resource for neurodegenerative disease research. However, achieving scalability for these technologies poses new challenges. For this reason, we’ve launched a rapid-action call inviting international research teams to address the most urgent issues in harmonisation and alignment in neuroimaging. The establishment of effective new guidelines and methodological frameworks will represent a critical step toward the full exploitation of brain imaging in neurodegenerative disease research.”

The following neurodegenerative diseases are included in the call:

Alzheimer’s disease and other dementias
Parkinson’s disease and PD‐related disorders
Prion diseases
Motor neuron diseases
Huntington’s disease
Spinocerebellar ataxia (SCA)
Spinal muscular atrophy (SMA)

Proposals must be submitted by 23:59H C.E.T. on March 10, 2016.

For more information about the call, please click here.

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

The unwanted formation of blood vessels — angiogenesis — in the brain is likely to be the cause of intractable walking and balance difficulties for people who suffer from Parkinson’s disease, according to new research.

Many people with Parkinson’s disease eventually experience walking and balance difficulties, despite adequate medication. Moreover, some patients cannot fully take dopamine-based medication, as dopamine can lead to side effects.

The current research findings verify similar data from a previous study by other researchers, which was performed on brain tissue from a small number of deceased patients.

“The strength of our study is the number of participants, and the fact that they are alive. Because many suffer from several parallel diseases at the final stage of their lives, it is difficult to analyse samples from deceased persons”, explains Oskar Hansson, reader at Lund University and consultant at Skåne University Hospital.

The findings, published in the journal Neurology, were made when the researchers used a broad approach when looking for mechanisms to increase understanding of how Parkinson’s disease works. “The measurements showed clear connections between markers of angiogenesis in the brain and walking or balance difficulties among the participants. We also noted an increased permeability of the blood-brain barrier, which leads to blood components potentially leaking into the brain and causing damage”, says Oskar Hansson.

Source: Lund University

As we age or develop neurodegenerative diseases such as Alzheimer’s, our brain cells may not produce sufficient energy to remain fully functional. Researchers have discovered that an enzyme called SIRT3 that is located in mitochondria — the cell’s powerhouse — may protect mice brains against the kinds of stresses believed to contribute to energy loss. Furthermore, mice that ran on a wheel increased their levels of this protective enzyme.

Researchers used a new animal model to investigate whether they could aid neurons in resisting the energy-depleting stress caused by neurotoxins and other factors. They found the following:

Mice models that did not produce SIRT3 became highly sensitive to stress when exposed to neurotoxins that cause neurodegeneration and epileptic seizures.
Running wheel exercise increased the amount of SIRT3 in neurons of normal mice and protected them against degeneration; in those lacking the enzyme, running failed to protect the neurons.
Neurons could be protected against stress through use of a gene therapy technology to increase levels of SIRT3 in neurons.

These findings suggest that bolstering mitochondrial function and stress resistance by increasing SIRT3 levels may offer a promising therapeutic target for protecting against age-related cognitive decline and brain diseases. The research team report their findings online Nov. 19 in the journal Cell Metabolism.

Source: Johns Hopkins Medicine

The blood-brain barrier has been non-invasively opened in a patient for the first time. Scientists used focused ultrasound to enable temporary and targeted opening of the blood-brain barrier (BBB).

Opening the blood-brain barrier in a localized region to deliver chemotherapy to a tumor is a predicate for utilizing focused ultrasound for the delivery of other drugs, DNA-loaded nanoparticles, viral vectors, and antibodies to the brain to treat a range of neurological conditions, including various types of brain tumors, Parkinson’s, Alzheimer’s and some psychiatric diseases.

The team infused the chemotherapy agent doxorubicin, along with tiny gas-filled bubbles, into the bloodstream of a patient with a brain tumor. They then applied focused ultrasound to areas in the tumor and surrounding brain, causing the bubbles to vibrate, loosening the tight junctions of the cells comprising the blood-brain barrier and allowing high concentrations of the chemotherapy to enter targeted tissues.

While the current trial is a first-in-human achievement, Dr. Kullervo Hynynen, senior scientist at the Sunnybrook Research Institute, has been performing similar pre-clinical studies for about a decade. His research has shown that the combination of focused ultrasound and microbubbles may not only enable drug delivery, but might also stimulate the brain’s natural responses to fight disease. For example, the temporary opening of the blood-brain barrier appears to facilitate the brain’s clearance of a key pathologic protein related to Alzheimer’s and improves cognitive function.

Source: Focused Ultrasound Foundation

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