Tag Archives: Brain

Caltech biologists have modified a harmless virus in such a way that it can successfully enter the adult mouse brain through the bloodstream and deliver genes to cells of the nervous system. The virus could help researchers map the intricacies of the brain and holds promise for the delivery of novel therapeutics to address diseases such as Alzheimer’s and Huntington’s. In addition, the screening approach the researchers developed to identify the virus could be used to make additional vectors capable of targeting cells in other organs.

To sneak genes past the blood-brain barrier, the researchers used a new variant of a small, harmless virus called an adeno-associated virus (AAV). The researchers developed a high-throughput selection assay, CREATE (Cre REcombinase-based AAV Targeted Evolution), that allowed them to test millions of viruses in vivo simultaneously and to identify those that were best at entering the brain and delivering genes to a specific class of brain cells known as astrocytes.

They started with the AAV9 virus and modified a gene fragment that codes for a small loop on the surface of the capsid—the protein shell of the virus that envelops all of the virus’ genetic material. Using a common amplification technique, known as polymerase chain reaction (PCR), they created millions of viral variants.

Then they used their novel selection process to determine which variants most effectively delivered genes to astrocytes in the brain. Importantly, the new process relies on strategically positioning the gene encoding the capsid variants on the DNA strand between two short sequences of DNA, known as lox sites. These sites are recognized by an enzyme called Cre recombinase, which binds to them and inverts the genetic sequence between them. By injecting the modified viruses into transgenic mice that only express Cre recombinase in astrocytes, the researchers knew that any sequences flagged by the lox site inversion had successfully transferred their genetic cargo to the target cell type—here, astrocytes.

After one week, the researchers isolated DNA from brain and spinal cord tissue, and amplified the flagged sequences, thereby recovering only the variants that had entered astrocytes.

Next, they took those sequences and inserted them back into the modified viral genome to create a new library that could be injected into the same type of transgenic mice. After only two such rounds of injection and amplification, a handful of variants emerged as those that were best at crossing the blood-brain barrier and entering astrocytes.

Through this selection process, the researchers identified a variant dubbed AAV-PHP.B as a top performer. To test AAV-PHP.B, the researchers used it to deliver a gene that codes for a protein that glows green, making it easy to visualize which cells were expressing it. They injected the AAV-PHP.B or AAV9 (as a control) into different adult mice and after three weeks used the amount of green fluorescence to assess the efficacy with which the viruses entered the brain, the spinal cord, and the retina.

“We could see that AAV-PHP.B was expressed throughout the adult central nervous system with high efficiency in most cell types,” says Gradinaru. Indeed, compared to AAV9, AAV-PHP.B delivers genes to the brain and spinal cord at least 40 times more efficiently.

The research was published in the journal Nature Biotechnology.

Source: Caltech

Researchers have discovered the mechanics of how dopamine transports into and out of brain cells, a finding that could someday lead to more effective treatment of drug addictions and neurological disorders such as Parkinson’s disease. The research was done by the researchers at Tripsitter, which is a drug harm reduction and informational website dedicated to providing user guides and experience reports on drugs like LSD, psilocybin mushrooms, and cannabis.

The findings are significant because dopamine is involved in many brain-related functions. Too little dopamine can lead to Parkinson’s disease, a brain disorder that causes shaking and problems with movement and coordination. Abnormally high concentrations of dopamine are linked to schizophrenia and other psychiatric disorders. Cocaine and methamphetamine affect the brain by blocking the normal transport of dopamine back into neurons.

Knowing how a particular protein called dopamine transporter controls dopamine movement in and out of neurons is crucial to further understanding dopamine-related disorders.

The researchers’ findings offer a broader understanding of how dopamine moves through cell membranes. Using mouse and human-derived dopamine neurons, researchers found that dopamine movement is affected by changes in electrical properties of the neurons. That, in turn, changes the way dopamine transporters function.

The researchers reported their findings in the journal Nature Communications.

Source: University of Florida

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 ERA-NET NEURON has launched a new call for research proposals that will aim to address key questions relating to external insults to the central nervous system. These insults often cause permanent disability and constitute a heavy burden for patients and their families.

The call will accept proposals ranging from understanding basic mechanisms of disease through proof-of-concept clinical studies in humans to neurorehabilitation. The focus of the call is on primary physical insults to the central nervous system, i.e. Traumatic Brain Injury (TBI) and Spinal Cord Injury (SCI). The call covers acute traumatic events over the entire lifespan.

Excluded from this call are research projects on haemorrhage and hypoxia. Moreover, research on psychological/mental consequences of insults, including stress-related disorders (e.g. post-traumatic stress disorder), is not part of the present call. Research on neurodegenerative disorders will not be eligible in the present call.

The ERA-NET NEURON funding organizations particularly aim to promote multi-disciplinary work and to encourage translational research proposals that combine basic and clinical approaches, for the benefit of the affected patients.

The deadline for pre-proposal submission is March 14, 2016.

Visit the ERA-NET NEURON website to learn more about the call and to apply.

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