Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Taking another Shot at RAGE to Tame Alzheimer’s

15.03.2012
Researchers have taken another crack at a promising approach to stopping Alzheimer’s disease that encountered a major hurdle last year.

In research published this week in the Journal of Clinical Investigation, scientists have developed a compound that targets a molecular actor known as RAGE, which plays a central role in mucking up the brain tissue of people with the disease.

Scientists at the University of Rochester Medical Center and the University of Southern California synthesized a compound that stops RAGE in mice – reversing amyloid deposits, restoring healthy blood flow in the brain, squelching inflammation, and making old, sick mice smarter. But the scientists caution that the work has a long way to go before it’s considered as a possible treatment in people.

A phase 2 study in 399 people of another compound designed to stop RAGE – which stands for Receptor for Advanced Glycation Endproducts – was halted prematurely in November when scientists had questions about the compound’s safety at high doses, and after early results indicated that the compound was not helping patients with Alzheimer’s disease.

Benjamin Miller, Ph.D., and Itender Singh, Ph.D.

Nevertheless, developing an effective RAGE inhibitor continues to lure scientists like Berislav Zlokovic, M.D., Ph.D., a neuroscientist formerly with the University of Rochester Medical Center and now at USC. Zlokovic headed the Rochester team that published its results in JCI.

“RAGE remains a phenomenally attractive target for Alzheimer’s therapy,” said Zlokovic.

“The benefits of blocking RAGE are even greater than has been realized. RAGE is central to many mechanisms that wreak havoc in the brains of people with Alzheimer’s disease. It turns out that when you inhibit RAGE, you block molecules central to creating inflammation in the brain, and that is a major problem with Alzheimer’s disease,” added Zlokovic, who is now director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute at USC.

Zlokovic was one of the first scientists to describe RAGE’s involvement in Alzheimer’s disease. Nearly a decade ago, in a paper in Nature Medicine, he showed that RAGE acts as a shuttle, ferrying amyloid beta from the blood into the brain. Since then, stopping RAGE has been an attractive but elusive goal for scientists seeking to create a new line of medications to treat Alzheimer’s disease.

In the latest work, Zlokovic and colleagues screened thousands of compounds for anti-RAGE activity and identified three that seemed promising. Then the team turned to chemists Benjamin Miller, Ph.D., and graduate student Nathan Ross. The pair analyzed the compounds’ molecular structures, then used that knowledge to create dozens of candidates likely to have activity against RAGE.

Several show promise, with one in particular, FPS-ZM1, especially robust at blocking RAGE. Crucially, it’s a very small molecule that crosses the blood-brain barrier and gets into the brain, where it’s needed. That’s not true of many potential RAGE inhibitors, including the three candidates that Zlokovic’s team had identified from the initial screen.

“It’s a very small molecule, but with a very big effect, which is just what you want,” said Miller. “And it’s easy to synthesize.”

The team tested FPS-ZM1 and other compounds in older mice, 15 to 17 months old, which are specially designed to accumulate amyloid beta in their brains quickly. Mice that received the compound:
Had much lowers levels of amyloid beta in the brain – 70 to 80 percent lower – because of the reduced effect of RAGE on amyloid beta;
Had much lower levels of inflammatory cells known as activated microglia – again, levels were reduced approximately 80 percent;
Had improved brain blood flow, almost back to the level of healthy mice.
Had improved learning capabilities that approached the levels of healthy mice.

The researchers were not surprised at the lower levels of amyloid beta, since RAGE allows amyloid beta to cross the brain/body barrier. But the scientists note that FPS-ZM1 affected RAGE’s operations in a number of important additional ways. The molecule lessened the activity of a molecule called NF kappa B, which causes inflammation like that seen in the brains of Alzheimer’s patients, and it reduced the activity of beta secretase, which plays a key role in the creation of amyloid beta.

Most important, the compound shows no evidence of toxicity in mice, even when used at concentrations hundreds of times higher than what would be used in a person.

The research is the culmination of several years of work by more than a dozen scientists at Rochester. The JCI paper has two co-first authors. Rashid Deane, Ph.D., research professor in the Center for Translational Neuromedicine, who headed the studies of blood flow in the brain, and Itender Singh, Ph.D., now a research assistant professor in the Department of Pediatrics, who headed the analysis of beta secretase activity and neuroinflammation. Singh also observed that the compound reduced oxidative stress in the brain, a process central to Alzheimer’s disease.

Other Rochester authors include Senior Instructor Abhay Sagare, Ph.D., Robert Bell, Ph.D., Barbra LaRue, Rachal Love, Sheldon Perry, Nicole Paquette, Richard Deane, Meenakshisundaram Thiyagarajan, Troy Zarcone, and Alan Friedman, Ph.D., assistant professor of Environmental Medicine. Gunter Fritz of the University of Freiburg in Germany also contributed.

Zlokovic is the founder of and an equity holder in Socratech, a company exploring new treatments for neurodegenerative diseases like Alzheimer’s. He also serves as a board member, and he and Deane are consultants to the company as well. The University of Rochester has a small equity interest in Socratech as well.

The work was funded by the National Institute on Aging.

For Media Inquiries:
Tom Rickey
(585) 275-7954
Email Tom Rickey

Tom Rickey | EurekAlert!
Further information:
http://www.urmc.rochester.edu

More articles from Health and Medicine:

nachricht NTU scientists build new ultrasound device using 3-D printing technology
07.12.2016 | Nanyang Technological University

nachricht How to turn white fat brown
07.12.2016 | University of Pennsylvania School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

NTU scientists build new ultrasound device using 3-D printing technology

07.12.2016 | Health and Medicine

The balancing act: An enzyme that links endocytosis to membrane recycling

07.12.2016 | Life Sciences

How to turn white fat brown

07.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>