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 Spanish scientists create a 3-D bioprinter to print human skin
24.01.2017 | Carlos III University of Madrid

nachricht Tracking movement of immune cells identifies key first steps in inflammatory arthritis
23.01.2017 | Massachusetts General Hospital

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: Scientists spin artificial silk from whey protein

X-ray study throws light on key process for production

A Swedish-German team of researchers has cleared up a key process for the artificial production of silk. With the help of the intense X-rays from DESY's...

Im Focus: Quantum optical sensor for the first time tested in space – with a laser system from Berlin

For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.

According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Breaking the optical bandwidth record of stable pulsed lasers

24.01.2017 | Physics and Astronomy

Choreographing the microRNA-target dance

24.01.2017 | Life Sciences

Spanish scientists create a 3-D bioprinter to print human skin

24.01.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>