Rutgers University – Alzheimer’s may be linked to defective brain cells spreading disease

Rutgers scientists say neurodegenerative diseases like Alzheimer’s and Parkinson’s may be linked to defective brain cells disposing toxic proteins that make neighboring cells sick

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In a study published in Nature, Monica Driscoll, distinguished professor of molecular biology and biochemistry, School of Arts and Sciences, and her team, found that while healthy neurons should be able to sort out and and rid brain cells of toxic proteins and damaged cell structures without causing problems, laboratory findings indicate that it does not always occur.

These findings, Driscoll said, could have major implications for neurological disease in humans and possibly be the way that disease can spread in the brain.

“Normally the process of throwing out this trash would be a good thing,” said Driscoll. “But we think with neurodegenerative diseases like Alzheimer’s and Parkinson’s there might be a mismanagement of this very important process that is supposed to protect neurons but, instead, is doing harm to neighbor cells.”

Driscoll said scientists have understood how the process of eliminating toxic cellular substances works internally within the cell, comparing it to a garbage disposal getting rid of waste, but they did not know how cells released the garbage externally.

“What we found out could be compared to a person collecting trash and putting it outside for garbage day,” said Driscoll. “They actively select and sort the trash from the good stuff, but if it’s not picked up, the garbage can cause real problems.”

Working with the transparent roundworm, known as the C. elegans, which are similar in molecular form, function and genetics to those of humans, Driscoll and her team discovered that the worms — which have a lifespan of about three weeks — had an external garbage removal mechanism and were disposing these toxic proteins outside the cell as well.

Ilija Melentijevic, a graduate student in Driscoll’s laboratory and the lead author of the study, realized what was occurring when he observed a small cloud-like, bright blob forming outside of the cell in some of the worms. Over two years, he counted and monitored their production and degradation in single still images until finally he caught one in mid-formation.

“They were very dynamic,” said Melentijevic, an undergraduate student at the time who spent three nights in the lab taking photos of the process viewed through a microscope every 15 minutes. “You couldn’t see them often, and when they did occur, they were gone the next day.”

Research using roundworms has provided scientists with important information on aging, which would be difficult to conduct in people and other organisms that have long life spans.

In the newly published study, the Rutgers team found that roundworms engineered to produce human disease proteins associated with Huntington’s disease and Alzheimer’s, threw out more trash consisting of these neurodegenerative toxic materials.

While neighboring cells degraded some of the material, more distant cells scavenged other portions of the diseased proteins.

“These finding are significant,” said Driscoll. The work in the little worm may open the door to much needed approaches to addressing neurodegeneration and diseases like Alzheimer’s and Parkinson’s.”

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Story Source:

Materials provided by Rutgers University. Original written by Robin Lally. Note: Content may be edited for style and length.

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Journal Reference:

1. Ilija Melentijevic, Marton L. Toth, Meghan L. Arnold, Ryan J. Guasp, Girish Harinath, Ken C. Nguyen, Daniel Taub, J. Alex Parker, Christian Neri, Christopher V. Gabel, David H. Hall, Monica Driscoll. C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. Nature, 2017; DOI: 10.1038/nature21362

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Rutgers University. “Alzheimer’s may be linked to defective brain cells spreading disease: Study finds toxic proteins doing harm to neighboring neurons.” ScienceDaily. ScienceDaily, 10 February 2017. <www.sciencedaily.com/releases/2017/02/170210131016.htm>.

Quantum dots could aid in fight against Parkinson’s

A large team of researchers with members from several institutions in the U.S., Korea and Japan has found that injecting quantum dots into the bloodstreams of mice led to a reduction in fibrils associated with Parkinson’s disease. In their paper published in the journal Nature Nanotechnology, the group describes their studies of the impact of quantum dots made of graphene on synuclein and what they found.

Quantum dots are particles that exist at the nanoscale and are made of semiconducting materials. Because they exhibit quantum properties, scientists have been conducting experiments to learn more about changes they cause to organisms when embedded in their cells. In this new effort, the researchers became interested in the idea of embedding quantum dots in synuclein cells.

Synucleins make up a group or family of proteins and are typically found in neural tissue.

One type, an alpha-synuclein, has been found to be associated with the formation of fibrils as part of the development of Parkinson’s disease. To see how such a protein might react when exposed to quantum dots, the researchers combined the two in a petri dish and watched what happened. They found that the quantum dots became bound to the protein, and in so doing, prevented it from clumping into fibrils. They also found that doing so after fibrils had already formed caused them to come apart. Impressed with their findings, the team pushed their research further.

Noting that quantum dots are small enough to pass through the blood/brain barrier, they injected quantum dots into mice with induced Parkinson’s disease and monitored them for several months. They report that after six months, the mice showed improvements in symptoms.

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Quantum dots in brain could treat Parkinson’s and Alzheimer’s diseases

The researchers suggest that quantum dots might have a similar impact on multiple ailments where fibrilization occurs, noting that another team had found that injecting them into Alzheimer’s mouse models produced similar results.

It is still not known if injecting similar or different types of quantum dots into human patients might have the same effect, they note. Nor is it known if doing so would have any undesirable side effects. Still, the researchers are optimistic about the idea of using quantum dots for treatment of such diseases and because of that, have initiated plans for testing with other animals—and down the road they are looking at the possibility of conducting clinical trials in humans.

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U of Michigan: ‘5-D protein fingerprinting’ could give insights into Alzheimer’s, Parkinson’s

This illustration depicts the device used to measure individual protein. The inset shows proteins (in red) flowing through a nanopore. Credit: University of Michigan

In research that could one day lead to advances against neurodegenerative diseases like Alzheimer’s and Parkinson’s, University of Michigan engineering researchers have demonstrated a technique for precisely measuring the properties of individual protein molecules floating in a liquid.

 

Proteins are essential to the function of every cell. Measuring their properties in blood and other body fluids could unlock valuable information, as the molecules are a vital building block in the body. The body manufactures them in a variety of complex shapes that can transmit messages between cells, carry oxygen and perform other important functions.

Sometimes, however, proteins don’t form properly. Scientists believe that some types of these misshapen proteins, called amyloids, can clump together into masses in the brain. The sticky tangles block normal cell function, leading to brain cell degeneration and disease.

But the processes of how amyloids form and clump together are not well understood. This is due in part to the fact that there’s currently not a good way to study them. Researchers say current methods are expensive, time-consuming and difficult to interpret, and can only provide a broad picture of the overall level of amyloids in a patient’s system.

The University of Michigan and University of Fribourg researchers who developed the new technique believe that it could help solve the problem by measuring an individual molecule’s shape, volume, electrical charge, rotation speed and propensity for binding to other molecules.

They call this information a “5-D fingerprint” and believe that it could uncover new information that may one day help doctors track the status of patients with neurodegenerative diseases and possibly even develop new treatments. Their work is detailed in a paper published in Nature Nanotechnology.

“Imagine the challenge of identifying a specific person based only on their height and weight,” said David Sept, a U-M biomedical engineering professor who worked on the project. “That’s essentially the challenge we face with current techniques. Imagine how much easier it would be with additional descriptors like gender, hair color and clothing. That’s the kind of new information 5-D fingerprinting provides, making it much easier to identify specific proteins.”

This illustration depicts a side view of proteins (blue) flowing through two electrically charged nanopores. Credit: University of Michigan

Michael Mayer, the lead author on the study and a former U-M researcher who’s now a biophysics professor at Switzerland’s Adolphe Merkle Institute, says identifying individual proteins could help doctors keep better tabs on the status of a patient’s disease, and it could also help researchers gain a better understanding of exactly how amyloid proteins are involved with neurodegenerative disease.

To take the detailed measurements, the research team uses a nanopore 10-30 nanometers wide—so small that only one protein molecule can fit through at a time. The researchers filled the nanopore with a salt solution and passed an electric current through the solution.

As a protein molecule tumbles through the nanopore, its movement causes tiny, measurable fluctuations in the electric current. By carefully measuring this current, the researchers can determine the protein’s unique five-dimensional signature and identify it nearly instantaneously.

“Amyloid molecules not only vary widely in size, but they tend to clump together into masses that are even more difficult to study,” Mayer said. “Because it can analyze each particle one by one, this new method gives us a much better window to how amyloids behave inside the body.”

Ultimately, the team aims to develop a device that doctors and researchers could use to quickly measure proteins in a sample of blood or other body fluid. This goal is likely several years off; in the meantime, they are working to improve the technique’s accuracy, honing it in order to get a better approximation of each protein‘s shape. They believe that in the future, the technology could also be useful for measuring proteins associated with heart disease and in a variety of other applications as well.

“I think the possibilities are pretty vast,” Sept said. “Antibodies, larger hormones, perhaps pathogens could all be detected. Synthetic nanoparticles could also be easily characterized to see how uniform they are.”

The study is titled “Real-time shape approximation and fingerprinting of single proteins using a nanopore.”

Explore further: Imaging technique measures toxicity of Alzheimer’s and Parkinson’s proteins

More information: Erik C. Yusko et al. Real-time shape approximation and fingerprinting of single proteins using a nanopore, Nature Nanotechnology (2016). DOI: 10.1038/nnano.2016.267

Journal reference: Nature Nanotechnology

Provided by: University of Michigan

Researchers Demonstrate Safe Interaction of Graphene with Nerve Cells

Graphene is a two-dimensional form of carbon, and successful demonstrations have been carried out by researchers to prove the possibility of interfacing graphene with nerve cells, or neurons, without affecting their integrity.

The demonstrations could help to develop graphene-based electrodes, which could be safely implanted into the brain. This study shows potential in restoring the sensory functions for individuals with Parkinson’s disease, epilepsy, amputees or paralyzed patients.

The Cambridge Graphene Centre and the University of Trieste in Italy together worked on this research, which was published in ACS Nano.

Other research teams have earlier demonstrated the possibility of using treated graphene to work with neurons. However very low signal to noise ratio was obtained from this interface. In this work, techniques were developed that allow the use of untreated graphene, and as a result they were able to retain the electrical conductivity of the material. This enables the graphene to function as a better electrode.

For the first time we interfaced graphene to neurons directly. We then tested the ability of neurons to generate electrical signals known to represent brain activities, and found that the neurons retained their neuronal signaling properties unaltered. This is the first functional study of neuronal synaptic activity using uncoated graphene based materials.

Professor Laura Ballerini, University of Trieste

It is possible to control some of the functions of the brain, by directly interfacing between the brain and the outside environment. For instance, it is possible to retrieve the sensory organs by evaluating the electrical impulses of the brain. This could help to control an amputee patient’s robotic arms or basic processes for paralyzed individuals, such as helping them with their speech and movement of objects surrounding them. It is also possible to control motor disorders like Parkinson’s disease or epilepsy when these electrical impulses are interfered with.

To make this possible, scientists have created electrodes that can be inserted deep into the human brain. These electrodes come into direct contact with the neurons and then send out electrical signals from the body to decode their meaning.

The issue that exists in the interface between neurons and electrodes is that the electrodes are not only expected to be extremely sensitive to electrical impulses, but they are also expected to be firm in the body without making changes in the tissue that is measured.

Often modern electrodes used for the tungsten-based or silicon-based interface suffer from complete or partial loss of signal over time. This occurs when scar tissues are created when the electrode is inserted, stopping the movement of the electrode with the natural movements of the brain due to its firm nature.

These issues can be solved using graphene due to its efficient stability, flexibility, conductivity, and biocompatibility within the body.

The researchers carried out experiments in the brain cell cultures of rats and concluded that interfacing with neurons was efficient in the case of untreated graphene electrodes. Based on the studies conducted on the neurons with electron microscopy and immunofluorescence, the researchers highlighted that the neurons continued to be healthy and transmitted normal electric impulses. Negative reactions that cause damage to the scar tissue were also not seen.

The research team considered this to be the first step in using pristine graphene-based materials instead of electrodes for a neuro-interface. The team plan to examine how different types of graphene, ranging from multiple layers to monolayers, are capable of affecting neurons. The researchers also plan to analyze whether changes made to the material properties of graphene can alter the neuronal excitability and synapses in unique ways.

Hopefully this will pave the way for better deep brain implants to both harness and control the brain, with higher sensitivity and fewer unwanted side effects.

Professor Laura Ballerini, University of Trieste

“We are currently involved in frontline research in graphene technology towards biomedical applications,” said Professor Maurizio Prato from the University of Trieste. “In this scenario, the development and translation in neurology of graphene-based high-performance biodevices requires the exploration of the interactions between graphene nano- and micro-sheets with the sophisticated signaling machinery of nerve cells. Our work is only a first step in that direction.”

These initial results show how we are just scratching the tip of an iceberg when it comes to the potential of graphene and related materials in bio-applications and medicine. The expertise developed at the Cambridge Graphene Centre allows us to produce large quantities of pristine material in solution, and this study proves the compatibility of our process with neuro-interfaces.

Professor Andrea Ferrari, Director of the Cambridge Graphene Centre

The research was financially supported by the European initiative, Graphene Flagship.

Source: http://www.cam.ac.uk/

Parkinson’s-like Symptoms Reversed in Lab Rats by Nanoparticle Drug

 As baby boomers age, the number of people diagnosed with Parkinson’s disease is expected to increase. Patients who develop this disease usually start experiencing symptoms around age 60 or older. Currently, there’s no cure, but scientists are reporting a novel approach that reversed Parkinson’s-like symptoms in rats. Their results, published in the journal ACS Nano, could one day lead to a new therapy for human patients.

Rajnish Kumar Chaturvedi, Kavita Seth, Kailash Chand Gupta and colleagues from the CSIR-Indian Institute of Toxicology Research note that among other issues, people with Parkinson’s lack dopamine in the brain. Dopamine is a chemical messenger that helps nerve cells communicate with each other and is involved in normal body movements. Reduced levels cause the shaking and mobility problems associated with Parkinson’s. Symptoms can be relieved in animal models of the disease by infusing the compound into their brains. But researchers haven’t yet figured out how to safely deliver dopamine directly to the human brain, which is protected by something called the blood-brain barrier that keeps out pathogens, as well as many medicines. Chaturvedi and Gupta’s team wanted to find a way to overcome this challenge.

 

The researchers packaged dopamine in biodegradable nanoparticles that have been used to deliver other therapeutic drugs to the brain. The resulting nanoparticles successfully crossed the blood-brain barrier in rats, released its dopamine payload over several days and reversed the rodents’ movement problems without causing side effects.

Explore further: Hunting down the trigger for Parkinson’s: Failing dopamine pump damages brain cells

More information: Trans-Blood Brain Barrier Delivery of Dopamine Loaded Nanoparticles Reverses Functional Deficits in Parkinsonian Rats, ACS Nano, Article ASAP, DOI: 10.1021/nn506408v

Abstract
Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson’s disease (PD), a neurodegenerative disorder. Therefore, in the present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6-OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats.

Journal reference: ACS Nano

 

Scientists uncover navigation system used by cancer, nerve cells

Duke University researchers have found a “roving detection system” on the surface of cells that may point to new ways of treating diseases like cancer, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

The cells, which were studied in nematode worms, are able to break through normal tissue boundaries and burrow into other tissues and organs—a crucial step in many normal developmental processes, ranging from embryonic development and wound-healing to the formation of new blood vessels.

But sometimes the process goes awry. Such is the case with metastatic cancer, in which cancer cells spread unchecked from where they originated and form tumors in other parts of the body.

“Cell invasion is one of the most clinically relevant yet least understood aspects of cancer progression,” said David Sherwood, an associate professor of biology at Duke.

 

Sherwood is leading a team that is investigating the molecular mechanisms that control cell invasion in both normal development and cancer, using a one-millimeter worm known as C. elegans.

At one point in C. elegans development, a specialized cell called the anchor cell breaches the dense, sheet-like membrane that separate the worm’s uterus from its vulva, opening up the worm’s reproductive tract.

Anchor cells can’t see, so they need some kind of signal to tell them where to break through. In a 2009 study, Sherwood and colleagues discovered that an extracellular cue called netrin orients the anchor cell so that it invades in the right direction.

In a new study appearing Aug. 25 in the Journal of Cell Biology, the team shows how receptors on the invasive cells essentially rove around the cell membrane “hunting” for the missing netrin signal that will guide the cell to the correct location.

The researchers used a video camera attached to a powerful microscope to take time-lapse movies of the slow movement of the C. elegans anchor cell during its invasion.

Their time-lapse analyses reveal that when netrin production is blocked, netrin receptors on the surface of the anchor cell periodically cluster, disperse and reassemble in a different region of the cell membrane. The receptors cluster alongside patches of actin filaments—thin flexible fibers that help cells change shape and form invasive protrusions –- that pop up in ea

“It’s kind of like a missile detection system,” Sherwood said.

Rather than the whole cell having to move around, its receptors move around on the outside of the cell until they get a signal. Once the receptors locate the netrin signal, they stabilize in the region of the cell membrane that is closest to the source of the signal.

The findings redefine decades-old ideas about how the cell’s navigation system works. “Cells don’t just passively respond to the netrin signal—they’re actively searching for it,” Sherwood said.

Given that netrin has been found to promote cell invasion in some of the most lethal cancers, the findings could lead to new treatment strategies. Disrupting the cell’s netrin detection system, for example, could prevent cancer cells from finding their way to the bloodstream or the lymphatic system and stop them from metastasizing, or becoming invasive and spreading throughout the body.

“One of the things we’re gearing up to do next are drug screens with our collaborators to see if we can block this detection system during invasion,” Sherwood said.

Scientists have also known for years that netrin plays a key role in wiring the brain and nervous system by guiding developing nerve cells as they grow and form connections.

This means the results could also point to new ways of treating neurological disorders like Parkinson’s and ALS and recovering from spinal cord injuries.

Tinkering with the cell’s netrin detection machinery, for example, may make it possible to encourage damaged cells in the central nervous system—which normally have limited ability to regenerate—to regrow.

Explore further: Scientists unravel mystery of brain cell growth