Highlighting a potential target in the treatment of multiple sclerosis (MS) and Alzheimer’s disease, new research suggests that triggering a protein found on the surface of brain cells may help slow the progression of these and other neurological diseases.

Working with mice, two research teams at Washington University School of Medicine in St. Louis independently linked the protein to the ability to clear debris from the brain. Such waste builds up both as a by-product of daily mental activities and as a result of misdirected immune system attacks on brain cells. If too much debris is present in the brain for too long, it can contribute to neurological disease.

In one study, scientists showed that Alzheimer’s brain plaques build up more slowly in mice that have a defective version of the TREM2 protein. In another, researchers showed that mice lacking the same protein had trouble cleaning up debris in the brain produced by damage to a protective coating on nerve cells. The problem is thought to occur in MS and other neurological disorders.

“We’ve been very interested in identifying ways to control naturally occurring mechanisms that help clean and repair the brain, and these new studies provide clear evidence that TREM2 could be just such a target,” said Laura Piccio, MD, PhD assistant professor of neurology and senior author of one of the studies.

Scientists are looking for ways to activate the protein to slow or prevent  damage caused by neurological disorders.

Previous studies have linked rare forms of the TREM2 gene to early-onset dementia and increased risk of Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

Scientists knew the protein was found on brain cells called microglia, which help maintain and repair the central nervous system. The new studies are among the first to provide clear evidence that the protein plays an integral role in at least some of these processes.

In Alzheimer’s disease, amyloid beta, a by-product of brain metabolism that is normally cleared from the brain, builds up to form plaques. Researchers in the laboratories of Marco Colonna, MD, the Robert Rock Belliveau MD Professor of Pathology, and John Cirrito, PhD, associate professor of neurology, bred mice lacking the gene with mice genetically engineered to have an Alzheimer’s-like condition.

First author Yaming Wang, PhD, a postdoctoral research scholar, monitored the build-up of amyloid plaques in the mice offspring as they aged and found that the absence of the gene significantly accelerated the accumulation of the plaques.

“We found that microglia cluster around amyloid plaques when TREM2 is present, presumably because the cells are getting ready to absorb the plaques and break them down,” said Colonna. “When TREM2 is absent, this clustering does not occur.”

In MS, misdirected immune cell attacks damage myelin, a protective coating on nerve cells, leaving myelin fragments in brain tissue. Failure to promptly remove this debris can worsen damage caused by the condition and inhibit repair mechanisms.

For the MS study, Piccio and colleagues at the John L. Trotter MS Center at Washington University School of Medicine and Barnes-Jewish Hospital gave a compound called cuprizone to mice that lacked the TREM2 gene. Cuprizone causes loss of myelin in a manner somewhat similar to that seen in people with MS.

“When we give normal mice this chemical, they can clear most of the myelin fragments from the brain,” Piccio said. “But when we gave cuprizone to mice that did not have the gene and looked at their brains four, six and 12 weeks later, we could still see evidence of damaged myelin.”

Motor coordination in these mice also was significantly more impaired after cuprizone exposure. This may reflect enhanced damage to brain cells resulting from the lingering presence of damaged myelin in the brain.

Colonna and his colleagues showed that TREM2 detects molecules associated with amyloid beta and with damaged neurons. They believe that the protein helps keep microglia from self-destructing as debris is cleared from the brain.

“This is a mechanism that is very common in immune cells,” he explained. “When a signal activates immune cells and they start attacking an invader or working to repair an injury, they start using energy very rapidly. If the cells do not receive a second signal confirming the need for their services, this increased energy usage will kill them.” University of Washington in St. Louis

Age-related loss of the Y chromosome (LOY) from blood cells, a frequent occurrence among elderly men, is associated with elevated risk of various cancers and earlier death.

This finding could help explain why men tend to have a shorter life span and higher rates of sex-unspecific cancers than women, who do not have a Y chromosome, said Lars Forsberg, PhD, lead author of the study and a geneticist at Uppsala University in Sweden.

LOY, which occurs occasionally as a given man’s blood cells replicate – and thus takes place inconsistently throughout the body – was first reported nearly 50 years ago and remains largely unexplained in both its causes and effects. Recent advances in genetic technology have allowed researchers to use a blood test to detect when only a small fraction of a man’s blood cells have undergone LOY.

Dr. Forsberg and colleagues studied blood samples from 1,153 elderly men aged 70 to 84 years, who were followed clinically for up to 40 years. They found that men whose samples showed LOY in a significant fraction of their blood cells lived an average of 5.5 years less than men whose blood was not affected by LOY. In addition, having undergone LOY significantly increased the men’s risk of dying from cancer during the course of the study. These associations remained statistically significant when results were adjusted for men’s age and other health conditions.

“Many people think the Y chromosome only contains genes involved in sex determination and sperm production,” said Jan Dumanski, MD, PhD, co-author on the study and a professor at Uppsala University. “In fact, these genes have other important functions, such as possibly playing a role in preventing tumours.” When LOY takes place, Y chromosome genes are not expressed, and this tumour prevention would be reduced.

Interestingly, LOY in blood cells is associated with many different cancers, including those outside of the blood system. This may be because Y chromosome genes enable blood cells to assist with immunosurveillance, the process by which the immune system detects and kills tumour cells to prevent cancer.

“Our hypothesis is that LOY disrupts the immunosurveillance normally conducted by blood cells, allowing tumours to grow unchecked and develop into cancer,” Dr. Forsberg said.

These findings suggest a new approach to early detection of cancer risk in men: a blood test to assess LOY. “LOY is not very dangerous in a small fraction of blood cells, but becomes increasingly predictive of cancer as more cells lose their Y chromosome,” Dr. Forsberg explained. “This takes years, so you’d have a window of time to do something to reduce your risk.”

The researchers are currently exploring LOY in more detail, including the effects of various lifestyle factors and other health conditions. They are also examining the frequency and consequences of LOY in different types of cells and throughout the life course. The American Society of Human Genetics

High blood pressure is a leading cause of death around the world, and its prevalence continues to rise. A study shows that a protein in the spleen called placental growth factor (PlGF) plays a critical role in activating a harmful immune response that leads to the onset of high blood pressure in mice. The findings pave the way for the development of more effective treatments for this common and deadly condition.

High blood pressure, also known as hypertension, affects more than 1 billion people worldwide and is a major risk factor for stroke, heart failure, and kidney diseases. Mounting evidence suggests that immune cells such as T cells contribute to the development of hypertension, but the underlying mechanisms have not been clear. Senior study author Giuseppe Lembo of IRCCS Neuromed and his team suspected that PlGF could be the missing link because it plays important roles in both the cardiovascular system and the immune system.

The researchers found support for this idea in the new study. Mice that were genetically engineered to lack PlGF did not develop hypertension after they were infused with angiotensin II–a hormone that normally increases blood pressure. These mice were also protected from hypertension-related heart and kidney damage, unlike genetically normal mice. Moreover, PlGF deficiency prevented T cells from leaving the spleen, entering the blood stream, and infiltrating the vessels and kidneys where hypertension was manifested. Additional experiments revealed that the nervous system controls levels of PlGF in the spleen, and PlGF in the spleen in turn is essential for the activation of T cells and the onset of hypertension.

‘In recent years, anti-PlGF monoclonal antibodies have been developed as a strategy to slow tumor growth and for age-related macular degeneration,’ says lead study author Daniela Carnevale. ‘The ongoing clinical trials testing humanized monoclonal antibodies directed to PlGF opens up the possibility of targeting it in hypertension too.’

‘There is a pressing need for new treatments to control and better target resistant hypertension,’ says Lembo. ‘PlGF is an appealing molecular therapeutic target because clinical tools to target this pathway already exist.’ EurekAlert

GNA Biosolutions GmbH (‘GNA’), a company developing ultra-fast diagnostic instruments for human pathogens, announced recently the start of the FILODIAG (Filovirus Diagnostics) project for developing an ultra-fast Ebola detection system based on GNA’s novel Laser PCR technology. GNA is leading a consortium of the Mendel University in Brno (Czech Republic), the Istituto Nazionale per le Malattie Infettive “Lazzaro Spallanzani” (Italy) and the Italian NGO EMERGENCY. The Project Number 115844 of this Ebola+ programme will be funded with EUR 2.3 million by the Innovative Medicines Initiative (IMI2).
There is an urgent need for fast and accurate diagnostic tests in the current and any future Ebola crisis. The rapid diagnosis of Ebola Virus Disease (EVD) during early and late stage of infection is a decisive step for risk assessment and for guidance to physicians to take the necessary decisions to limit the spread of the infection, and to safely nurse the infected patients. While fast and easy-to-use tests usually rely on immuno-diagnostic approaches, they typically lack high sensitivity and specificity. The gold standard for accurate diagnostics is Real-Time PCR but this procedure requires special laboratory facilities and a long processing time of up to several hours.  The aim of the FILODIAG project is to deliver a potentially multiplexed diagnostic system fast enough for point-of-need testing of incoming patients as well as at critical infrastructure checkpoints like airports by withdrawal of blood, or less invasive fluids, such as saliva or urine.
The core technology being used is based on GNA’s laser-heated nanoparticles (Laser PCR) that helps to overcome the time-limiting step of heating and cooling the reaction sample in conventional PCR reactions. GNA have revolutionized this standard procedure by inducing the necessary temperature cycles with laser-heated nanoparticles that can be heated and cooled more than a million times faster than in conventional PCR. GNA has already performed Ebola Laser PCR assays that detect 10 target copies of synthetic nucleotides, corresponding to the Ebola genome sequence, in less than 12 minutes.
Members of the Department of Chemistry and Biochemistry at Mendel University, Brno, will work on integrating the sample preparation with virus-binding magnetic particles. Leading scientist Dr. Vojtech Adam explains: “We will synthesize, characterize and modify the surfaces of nanomaterials to achieve a highly specific binding of viral proteins that will allow for a faster preparation step from patient samples.”
Project coordinator Dr. Lars Ullerich, a Managing Director of GNA, said: “We are working with our international partners to develop a highly sensitive and specific Laser PCR assay based on saliva, urine or blood for Ebola detection. Our proprietary Laser PCR with ten times faster cycles allows us to utilize the gold standard of PCR also in Ebola diagnostics. Together with a label-free detection, the test results will be available in less than 15 minutes. Our Pharos400 system can already detect other highly dangerous pathogens within three minutes and a rapid, simple testing workflow will be crucial to deliver effective support in the management of Ebola outbreaks.”
Dr. Antonino Di Caro, director of microbiology, National Institute for Infectious Diseases “Lazzaro Spallanzani”, will test the device and the assay in a biosafety level 4 laboratory in advance of EMERGENCY conducting field testing in their recently established Ebola treatment centre in Sierra Leone.
The IMI2 Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. IMI2 has recently launched the programme Ebola+, in which eight funded projects have been announced, including FILODIAG, and two further projects with a diagnostic focus. The FILODIAG project will present future progress on www.filodiag.eu.

www.gna-bio.com

New research points to malfunctioning tau, not amyloid-beta (Abeta) plaque, as the seminal event that spurs neuron death in disorders such as Alzheimer’s disease. The finding, which dramatically alters the prevailing theory of Alzheimer’s development, also explains why some people with plaque build-up in their brains don’t have dementia.

Neuronal death happens when tau, found inside neurons, fails to function. Tau’s role is to provide a structure — like a train track —inside brain neurons that allows the cells to clear accumulation of unwanted and toxic proteins.

“When tau is abnormal, these proteins, which include Abeta, accumulate inside the neurons,” explains the study’s senior investigator, Charbel E-H Moussa, MB, PhD, assistant professor of neuroscience at Georgetown University Medical Center. “The cells start to spit the proteins out, as best they can, into the extracellular space so that they cannot exert their toxic effects inside the cell. Because Abeta is ‘sticky,’ it clumps together into plaque,” Moussa says.

He says his study suggests the remaining Abeta inside the neuron (that isn’t pushed out) destroys the cells, not the plaques that build up outside. “When tau does not function, the cell cannot remove the garbage, which at that point includes Abeta as well as tangles of non-functioning tau, and the cell dies. The Abeta released from the dead neuron then sticks to the plaque that had been forming.”

Moussa’s experiments in animal models also show less plaques accumulate outside the cell when tau is functioning; when tau was reintroduced into neurons that did not have it, plaques did not grow.

Malfunctioning tau can occur due to errant genes or through aging. As individuals grow older, some tau can malfunction while enough normal tau remains to help clear the garbage. In these cases, the neurons don’t die, he says. “That explains the confusing clinical observations of older people who have plaque build-up, but no dementia,” Moussa says.

Moussa has long sought a way to force neurons to clean up their garbage. In this study, he shows that nilotinib, a drug approved to treat cancer, can aid in that process. Nilotinib helps the neuron clear garbage, but requires some functional tau, he says.

“This drug can work if there is a higher percentage of good to bad tau in the cell,” Moussa says. “There are many diseases of dementia that have malfunctioning tau and no plaque accumulation, such as frontal temporal dementia linked to Parkinsonism,” Moussa says. “The common culprit is tau, so a drug that helps tau do its job may help protect against progression of these diseases.” Georgetown University Medical Center