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:
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 | EurekAlert!
A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital
Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...
Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.
A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...
20.04.2017 | Event News
18.04.2017 | Event News
03.04.2017 | Event News
21.04.2017 | Physics and Astronomy
21.04.2017 | Health and Medicine
21.04.2017 | Physics and Astronomy