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 Potential seen for tailoring treatment for acute myeloid leukemia
10.12.2018 | University of Washington Health Sciences/UW Medicine

nachricht UC San Diego researchers develop sensors to detect and measure cancer's ability to spread
06.12.2018 | University of California - San Diego

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: Researchers develop method to transfer entire 2D circuits to any smooth surface

What if a sensor sensing a thing could be part of the thing itself? Rice University engineers believe they have a two-dimensional solution to do just that.

Rice engineers led by materials scientists Pulickel Ajayan and Jun Lou have developed a method to make atom-flat sensors that seamlessly integrate with devices...

Im Focus: Three components on one chip

Scientists at the University of Stuttgart and the Karlsruhe Institute of Technology (KIT) succeed in important further development on the way to quantum Computers.

Quantum computers one day should be able to solve certain computing problems much faster than a classical computer. One of the most promising approaches is...

Im Focus: Substitute for rare earth metal oxides

New Project SNAPSTER: Novel luminescent materials by encapsulating phosphorescent metal clusters with organic liquid crystals

Nowadays energy conversion in lighting and optoelectronic devices requires the use of rare earth oxides.

Im Focus: A bit of a stretch... material that thickens as it's pulled

Scientists have discovered the first synthetic material that becomes thicker - at the molecular level - as it is stretched.

Researchers led by Dr Devesh Mistry from the University of Leeds discovered a new non-porous material that has unique and inherent "auxetic" stretching...

Im Focus: The force of the vacuum

Scientists from the Theory Department of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science (CFEL) in Hamburg have shown through theoretical calculations and computer simulations that the force between electrons and lattice distortions in an atomically thin two-dimensional superconductor can be controlled with virtual photons. This could aid the development of new superconductors for energy-saving devices and many other technical applications.

The vacuum is not empty. It may sound like magic to laypeople but it has occupied physicists since the birth of quantum mechanics.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

Expert Panel on the Future of HPC in Engineering

03.12.2018 | Event News

 
Latest News

Small but ver­sat­ile; key play­ers in the mar­ine ni­tro­gen cycle can util­ize cy­anate and urea

10.12.2018 | Life Sciences

New method gives microscope a boost in resolution

10.12.2018 | Physics and Astronomy

Carnegie Mellon researchers probe hydrogen bonds using new technique

10.12.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>