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Technion breakthrough opens new avenues for Alzheimer’s cure

HAIFA, ISRAEL and NEW YORK (July 10, 2014) – Alzheimer’s disease affects approximately 5.2 million people in the United States alone, and it is the nation’s sixth leading cause of death.  A cure for this insidious killer has so far proven elusive, but that could soon change as a result of a breakthrough at the Technion-Israel Institute of Technology that sheds light on a key mechanism in the accumulation of protein plaques in the tissue of Alzheimer’s disease patients.

The findings were published online this week by Nature Chemical Biology.

“Proteins that constitute major building blocks of our body cells continuously pass through quality control,” explains team leader Prof. Michael Glickman, of the Faculty of Biology. “Defective proteins are sent to the proteasome, a molecular machine (found in all of our cells) that eliminates defective proteins by recycling them back to their building blocks. But a small number of them slip through this process. Proteins that evade the proteasome accumulate, and may be harmful when they reach a critical mass, which is often the case at an advanced age.”

The researchers’ breakthrough findings are centered on UBB +1, a mutation prevalent in Alzheimer’s disease patients.  The mutation impairs a protein called ubiquitin* that marks other proteins to be dismantled at the proteasome.

Previously, the prevailing view among scientists was that UBB +1 impairs the functioning of the proteasome itself.  But in her doctoral dissertation under the guidance of Prof. Glickman, Dr. Daria Krutauz found that in the presence of UBB+1, damaged proteins are apprehended on their way to the proteasome, and accumulate without reaching their final recycling destination.  As a result, they have more opportunity to form the deadly plaque associated with Alzheimer’s disease.

“Because our findings run contrary to what was previously believed, this discovery opens new venues for intervention in the hope of developing a cure for Alzheimer’s disease,” says Prof. Glickman.

The research team was comprised of Prof. Michael Glickman, Dr. Daria Krutauz and Lab Manager Noa Reis, in collaboration with team members in the labs of Prof. David Fushman at the University of Maryland, Prof. Steve Gygi at Harvard Medical School and Prof. Ashraf Brik at Ben Gurion University.

In the photos: Prof. Michael Glickman, Dr. Daria Krutauz

* In 2004, Distinguished Professors Avram Hershko and Aaron Ciechanover of the Technion, and Prof. Ernie Rose from the Fox Chase Institute were awarded the Nobel Prize in chemistry for their discovery of ubiquitin.

Iron Dome, developed by Technion graduates, again defends Israel.

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Assistant Professor Avi Avital is taming rats to detect explosives and construct animal models as a working platform for the treatment of diseases such as schizophrenia.

Assistant Professor Avi Avital from the Technion’s Rappaport Faculty of Medicine, is training rats in an attempt to build (along with Professors Moshe Gabish and John Finberg) – a working model for the treatment of neurodegenerative diseases such as Parkinson’s and Huntington. He recently built a working model to validate symptoms of schizophrenia: “We gave rats a low sub-anesthetic dose of ketamine (a veterinary anesthetic) and exposed them to stress to build a working model for the treatment of schizophrenia – for an understanding of the factors responsible for disease outbreak and experimental platforms for drug development.”

איור המתאר את מעבדתו ואופן עבודתו של פרופוסר משנה אביטל

As part of an applied research study, Assistant Professor Avital succeeded in taming rats to detect explosives. “Rats have a highly developed sense of smell and we succeeded in taming them to identify scents of explosive materials,” he said. “The insights from a study of rat models are being implemented in dog training in a collaborative study with the Israel Ministry of Defense and the United States Army (USA).”

“In an extensive mapping study we conducted, we exposed rats to stress at different periods of their lives, and we found that the critical period for exposure to stress is during the same transition period between childhood and adolescence in humans,” he said.

On the account of an NIH grant from the American Defense Department, Assistant Professor Avital built a sophisticated laboratory of behavioral biology, which is studying rats mainly in the area of attention and social interaction, in combination with behavioral aspects of physiological and pharmacological research. In parallel of performing his clinical research, which he conducts at the Emek Medical Center in Afula, he continues his work with dogs. Recently, he developed a device that simulates explosive materials as part of a systematic and safe dog training process. In this field he newly demonstrated the importance of the link between stress level and attention of a dog’s customary ability to execute various tasks. He also found that if the dog detects one type of explosive, he is capable of generalizing and identifying other types of explosives. “We have shown that this ability to generalize is found in the same brain region of both dogs and rats,” he explained.

Assistant Professor Avital developed a way to train rats through behavioral shaping procedures. He clothes rats with a “vest” that is connected to tiny metals imbedded under the rat’s skin (using a minimal-pain procedure). The rat feels a light tap – he taught them that when the tap is felt on the right hand side to turn left, and vice versa. When tapping both shoulders, the rat will stop, etc.

In the study investigating social cooperation, Assistant Professor Avital built a labyrinth that is controlled automatically by software and a camera through which rats learn social cooperation. “Female rats cooperate better than males,” he emphasized.

Assistant Professor Avital’s work is unique because it is beyond translational science (circumspect conclusions of a rat model to humans); he conducts half translational science, that is: he makes inferences from one animal (rats) to another (dogs). Using behavioral, physiological and pharmacological methods, Assistant Professor Avital focuses on attention and social cooperation in all research levels aforementioned.

In the photo:

A lab rat and an illustration depicting the laboratory and Assistant Professor Avital’s work methods.

The video displays a rat dressed in a “vest.”

Technion researchers are part of an international team of scientists who discovered a swiftly moving gas streamer eclipsing a supermassive black hole

An international team of astronomers, including Prof. Ehud Behar and Dr. Shai Kaspi from the Technion’s Physics Department has discovered that the supermassive black hole at the heart of the galaxy NGC 5548 has recently undergone strange, unexpected behavior rarely seen in the heart of active galaxies. The researchers detected a clumpy gas stream flowing quickly outward and blocking 90 percent of the X-rays emitted by the supermassive black hole at the center of the galaxy.

This activity may provide new insights into the interaction of supermassive black holes and their host galaxies.

This discovery was accomplished through an intensive observing campaign with the major ESA and NASA space observatories: XMM-Newton, the Hubble Space Telescope, Swift, NuSTAR, Chandra, and INTEGRAL. An international team led by scientist Jelle Kaastra, of the SRON Netherlands Institute for Space Research conducted the most extensive monitoring campaign ever of an active galaxy in 2013 and 2014.

ציור של האזור המרכזי של NGC 5548 (לא בקנ”מ מדויק). הדיסקה סביב החור השחור מפיצה קרני X וקרינה אולטרה-סגולה, אופטית ואינפרה-אדומה ומוקפת בטבעת אבק. הקווים הקמורים מציינים את זרם הגז הנע לאורך קווי השדה המגנטי של הרוח של דיסקת הספיחה. האזור המעורפל עשוי מתערובת של גז מיונן ובתוכו חלקים צפופים וקרים יותר, והוא קרוב יותר לאזור הפנימי של פליטת קרינת אולטרה-סגול. אזור הקו הצר וקולט-החום נמצאים יותר בחוץ.

“We have been observing outflows from active galaxies in detail for over a decade, but have yet to crack their operating mechanism. The present observations are the first time we apparently caught the launch of such a wind and were able to measure its high velocity. ” said Ehud Behar a world renown expert on X-ray spectroscopy of outflows from active galaxies.

The researchers say that this is the first direct evidence for the long-predicted shielding process that is needed to accelerate powerful gas streams, or “winds,” to high speeds. The team reports that this is a milestone in understanding how supermassive black holes interact with their host galaxies.

These results are being published in the June issue of Science magazine.

Matter falling onto a black hole gets heated and emits X-rays and ultraviolet radiation. The ultraviolet radiation can launch winds outward. The winds may be so strong that they can blow off gas that otherwise would have fallen onto the black hole. Black hole winds can therefore regulate both the growth of the black hole and its galaxy. If the falling gas feeds the black hole, the newly discovered outflow is evidence for its eating disorder.

But the winds may only come into existence if their starting point is shielded from X-rays. The newly discovered gas stream in the archetypal Seyfert galaxy NGC 5548 — one of the best-studied sources of this type over the past half-century — provides this protection. It appears that the shielding has been going on for at least three years.

Right after the Hubble Space Telescope had observed NGC 5548 on June 22, 2013, the team discovered dramatic changes since the last observation with Hubble in 2011. They observed signatures of much colder gas than was present before, indicating that the wind had cooled down, due to a strong decrease of ionizing X-ray radiation from the nucleus.

After combining and analyzing data from the six observatories, the team was able to put the pieces of the puzzle together. Supermassive black holes in the nuclei of active galaxies, such as NGC 5548, expel large amounts of matter through powerful winds of ionized gas. For instance, the persistent wind of NGC 5548, known for two decades, reaches velocities exceeding 1000 km/s.

But now a new wind has arisen, much stronger and faster than the persistent wind. “The new wind reaches speeds of up to 5,000 kilometers per second but is much closer to the nucleus than the persistent wind,” Kaastra said. “The new gas outflow blocks 90 percent of the low-energy X-rays that come from very close to the black hole, and it obscures up to a third of the region that emits the ultraviolet radiation at a few light-days distance from the black hole.”

Further information

These results are published in Science:

http://www.sciencemag.org/content/early/2014/06/18/science.1253787.full

“A fast and long-lived outflow from the supermassive black hole in NGC 5548”, by Kaastra et al.

Team:

The team consists of Jelle Kaastra (SRON Utrecht, The Netherlands), Jerry Kriss (Space Telescope Science Institute, Baltimore, USA), Massimo Cappi (INAF-IASF Bologna, Italy), Missagh Mehdipour (SRON Utrecht, The Netherlands), Pierre-Olivier Petrucci (Univ. Grenoble Alpes, CNRS, France), Katrien Steenbrugge (Universidad Católica del Norte, Antofagasta, Chile), Nahum Arav (Virginia Tech, Blacksburg, USA), Ehud Behar (Technion-Israel Institute of Technology, Haifa, Israel), Stefano Bianchi (Università degli Studi Roma Tre, Italy), Rozenn Boissay (University of Geneva , Switzerland), Graziella Branduardi-Raymont (MSSL/UCL, Holmbury St. Mary, UK), Carter Chamberlain (Virginia Tech, Blacksburg, USA ), Elisa Costantini (SRON Utrecht, The Netherlands), Justin Ely (Space Telescope Science Institute, Baltimore, USA), Jacobo Ebrero (ESA, Spain), Laura Di Gesu (SRON Utrecht, The Netherlands), Fiona Harrison (California Institute of Technology, Pasadena, USA), Shai Kaspi (Technion-Israel Institute of Technology, Haifa, Israel), Julien Malzac (Université de Toulouse, France), Barbara De Marco (Max-Planck-Institut für extraterrestrische Physik, Garching, Germany), Giorgio Matt (Università degli Studi Roma Tre, Italy), Paul Nandra (Max-Planck-Institut für extraterrestrische Physik, Garching, Germany), Stéphane Paltani (University of Geneva , Switzerland), Renaud Person (St. Jorioz, France), Brad Peterson (Ohio State University, Columbus, USA), Ciro Pinto (University of Cambridge, UK), Gabriele Ponti (Max-Planck-Institut für extraterrestrische Physik, Garching, Germany), Francisco Pozo Nuñez (Ruhr-Universität Bochum, Gernmany), Alessandra De Rosa (INAF/IAPS, Roma, Italy), Hiromi Seta (Rikkyo University, Tokyo, Japan), Francesco Ursini (University of Grenoble, CNRS, France), Cor de Vries (SRON Utrecht, The Netherlands), Dom Walton (California Institute of Technology, Pasadena, USA), Megan Whewell (MSSL/UCL, Holmbury St. Mary, UK).

Movie:

A new creation by Renaud Person, one of the Worlds Director of the famous video game Assassin’s Creed © Ubisoft. The movie brings us in a journey to the inner regions of NGC5548, and helps us in visualizing the findings presented in this study.

www.sron.nl/~kaastra/press5548/NGC5548_Obscurer_H264.mov ‬‬

An animated journey through the active galaxy NGC 5548.

At its center is a supermassive black hole that is 40 million times heavier than our Sun, all concentrated in a region smaller than the Earth’s orbit around the Sun. Gas swirls around this black hole and is sucked into it, heating up its surroundings and producing strong energetic X-ray radiation. This X-ray hot corona is fuelled through a rapidly rotating accretion disk. The disk also produces strong patchy winds of warm gas that is thrown out into space. It contains denser parts that may obscure the X-rays emitted in the direction towards the Earth, shown by the green line. Further outwards we see the winds produced by the outer parts of the rotating disk, where the so-called broad line clouds are. At light years away from the black hole the warm winds also absorb some of the X-ray and ultraviolet light from the nucleus. These winds can cool down when the obscuring inner clouds block the light from the nucleus. The power emitted by the nucleus is so strong that it affects major parts of the host galaxy. The galaxy has a size of hundred thousand light years and is at a distance of 240 million light years away from us.

Technion Scientists Develop ‘Test Tube Brain Tissue’ that Provides a 3-D View of Neural Activity

The new ‘Optonet’ cultures could enable a better understanding of complex activity within neural networks

Neural cells grown on laboratory plates (two-dimensional neural cultures) constitute a convenient model for many studies in the field of neuroscience and medicine. Their main advantage is the relative simplicity by which they can be used to examine physiological changes in neural cells’ activity patterns caused by changes in their environment. However, the shortcomings of these simple 2D cultures is that they contain only a single layer of cells, and do not exhibit the complex three-dimensional network connectivity found in real brains. Previous attempts to develop 3D models for studying the central nervous system have met with limited success, mainly due to the high complexity of developing a 3D culture capable of simulating brain tissue as well as challenges associated with developing methods for observing network activity in three dimensions. Technion researchers led by Professor Shy Shoham from the Department of Biomedical Engineering now report in Nature Communications that they were able to develop, for the first time, three dimensional cell networks that can simulate complex aspects of brain activity, which could provide a better access for understanding the physiology of the central nervous system.

המחשה של המיקרוסקופ אותו בנינו במעבדה. על ידי שימוש בטכניקה מתקדמת, הנקראת מיקוד זמני, ניתן לדמות ביעילות ובמהירות איזורים גדולים בתרבית. כל נקודה בתרבית מצולמת 10 פעמים בשניה, מהירות המאפשרת לזהות כל שינוי בפעילות התאים.

The Editors of Nature Communications note that three-dimensional neural networks represent a promising model of complex neural tissue, which may lead to a better understanding of the structure and function of the brain, and that the Technion researchers also present an advanced method for viewing the neural activity of the engineered culture using a fast microscopy system they developed.

Prof. Shoham and his research team, which included Dr. Hod Dana, Dr. Anat Marom, Shir Paluch, Roman Dvorkin and Dr. Inbar Brosh, explain that they grew the advanced culture in a clear gel that supports cellular growth and allows the cells to bind and form neural networks. “By optimizing the culturing conditions we achieved cellular density and composition similar to those found in the human brain, and were able to demonstrate the formation of connections between cells and of networks that maintain neural activity,” says Dr. Marom. To enable the study of network activity in 3D, optical tools were used: nerve cells in the cultures were genetically altered making it possible to view ongoing network activity through a fluorescence microscope, earning them the nickname “Optonets”.

To view cell activity in 3-D, the researchers developed an advanced imaging system that uses ‘temporal focusing’– a non-linear optical technique developed nearly a decade ago at the Weizmann Institute of Science. “The hybrid SLITE imaging system we developed is a significant step forward in improving research capabilities for viewing the activities of multiple brain cells in space and time through which we may be able to reach insights about brain activity,” explains Dr. Dana.

“Through complementary advances in microscopy and in neural tissue engineering we demonstrated an unprecedented ability to view more than a thousand cells within developing neural networks, exhibiting complex spontaneous activity patterns. These innovations open new windows of opportunity for further developments in the field of neural interfaces and other applications for 3-D engineered networks, ranging from basic brain research to the examination of the impact of neurological drugs on nerve cell activity”, summarizes Prof. Shoham.

In the photos:

1. Illustration of the Technion team’s SLITE microscope, which uses advanced optics to image the 3D culture at a rate of 10 images per second – fast enough to follow neural activity.

2. Optonets placed over text to illustrate their translucency; the images were taken on different days during the culture’s growth and development.

Clip:

The video shows activity imaged in a culture region containing approximately 1,000 cells, revealing synchronized spontaneous activity bursts in adjacent groups of cells. Neural activity is indicated by changes in the cells’ color.