Featured Research

from universities, journals, and other organizations

Potential Alzheimer's drug prevents abnormal blood clots in brain

Date:
June 27, 2014
Source:
Rockefeller University
Summary:
The brains of Alzheimer's mice treated with the compound RU-505 showed less inflammation and improved blood flow than those of untreated mice. The treated mice also performed better on memory tests, researchers report. For more than a decade, potential Alzheimer's drugs have targeted amyloid-, but, in clinical trials, they have either failed to slow the progression of the disease or caused serious side effects. However, by targeting the protein's ability to bind to a clotting agent in blood, the work in one lab offers a promising new strategy.

Treatment with the compound RU-505 improved the chronic and damaging inflammation (red) in the brains of mice exhibiting Alzheimer's (top), as compared to Alzheimer's mice that went untreated (bottom).
Credit: Strickland Lab, The Rockefeller University

Without a steady supply of blood, neurons can't work. That's why one of the culprits behind Alzheimer's disease is believed to be the persistent blood clots that often form in the brains of Alzheimer's patients, contributing to the condition's hallmark memory loss, confusion and cognitive decline.

Related Articles


New experiments in Sidney Strickland's Laboratory of Neurobiology and Genetics at Rockefeller University have identified a compound that might halt the progression of Alzheimer's by interfering with the role amyloid-β, a small protein that forms plaques in Alzheimer's brains, plays in the formation of blood clots. This work is highlighted in the July issue of Nature Reviews Drug Discovery.

For more than a decade, potential Alzheimer's drugs have targeted amyloid-β, but, in clinical trials, they have either failed to slow the progression of the disease or caused serious side effects. However, by targeting the protein's ability to bind to a clotting agent in blood, the work in the Strickland lab offers a promising new strategy, according to the highlight, which will be published in print on July 1.

This latest study builds on previous work in Strickland's lab showing amyloid-β can interact with fibrinogen, the clotting agent, to form difficult-to-break-down clots that alter blood flow, cause inflammation and choke neurons.

"Our experiments in test tubes and in mouse models of Alzheimer's showed the compound, known as RU-505, helped restore normal clotting and cerebral blood flow. But the big pay-off came with behavioral tests in which the Alzheimer's mice treated with RU-505 exhibited better memories than their untreated counterparts," Strickland says. "These results suggest we have found a new strategy with which to treat Alzheimer's disease."

RU-505 emerged from a pack of 93,716 candidates selected from libraries of compounds, the researchers write in the June issue of the Journal of Experimental Medicine. Hyung Jin Ahn, a research associate in the lab, examined these candidates with a specific goal in mind: Find one that interferes with the interaction between fibrinogen and amyloid-β. In a series of tests that began with a massive, automated screening effort at Rockefeller's High Throughput Resource Center, Ahn and colleagues winnowed the 93,000 contenders to five. Then, test tube experiments whittled the list down to one contender: RU-505, a small, synthetic compound. Because RU-505 binds to amyloid-β and only prevents abnormal blood clot formation, it does not interfere with normal clotting. It is also capable of passing through the blood-brain barrier.

"We tested RU-505 in mouse models of Alzheimer's disease that over-express amyloid- β and have a relatively early onset of disease. Because Alzheimer's disease is a long-term, progressive disease, these treatments lasted for three months," Ahn says. "Afterward, we found evidence of improvement both at the cellular and the behavioral levels."

The brains of the treated mice had less of the chronic and harmful inflammation associated with the disease, and blood flow in their brains was closer to normal than that of untreated Alzheimer's mice. The RU-505-treated mice also did better when placed in a maze. Mice naturally want to escape the maze, and are trained to recognize visual cues to find the exit quickly. Even after training, Alzheimer's mice have difficulty in exiting the maze. After these mice were treated with RU-505, they performed much better.

"While the behavior and the brains of the Alzheimer's mice did not fully recover, the three-month treatment with RU-505 prevents much of the decline associated with the disease," Strickland says.

The researchers have begun the next steps toward developing a human treatment. Refinements to the compound are being supported by the Robertson Therapeutic Development Fund and the Tri-Institutional Therapeutic Discovery Institute. As part of a goal to help bridge critical gaps in drug discovery, these initiatives support the early stages of drug development, as is being done with RU-505.

"At very high doses, RU-505 is toxic to mice and even at lower doses it caused some inflammation at the injection site, so we are hoping to find ways to reduce this toxicity, while also increasing RU-505's efficacy so smaller doses can accomplish similar results," Ahn says.


Story Source:

The above story is based on materials provided by Rockefeller University. Note: Materials may be edited for content and length.


Journal Reference:

  1. H. J. Ahn, J. F. Glickman, K. L. Poon, D. Zamolodchikov, O. C. Jno-Charles, E. H. Norris, S. Strickland. A novel A-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice. Journal of Experimental Medicine, 2014; 211 (6): 1049 DOI: 10.1084/jem.20131751

Cite This Page:

Rockefeller University. "Potential Alzheimer's drug prevents abnormal blood clots in brain." ScienceDaily. ScienceDaily, 27 June 2014. <www.sciencedaily.com/releases/2014/06/140627163748.htm>.
Rockefeller University. (2014, June 27). Potential Alzheimer's drug prevents abnormal blood clots in brain. ScienceDaily. Retrieved October 26, 2014 from www.sciencedaily.com/releases/2014/06/140627163748.htm
Rockefeller University. "Potential Alzheimer's drug prevents abnormal blood clots in brain." ScienceDaily. www.sciencedaily.com/releases/2014/06/140627163748.htm (accessed October 26, 2014).

Share This



More Mind & Brain News

Sunday, October 26, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Academic Scandal Shocks UNC

Academic Scandal Shocks UNC

AP (Oct. 23, 2014) A scandal involving bogus classes and inflated grades at the University of North Carolina was bigger than previously reported, a new investigation found. (Oct. 23) Video provided by AP
Powered by NewsLook.com
Working Mother Getaway: Beaches Turks & Caicos

Working Mother Getaway: Beaches Turks & Caicos

Working Mother (Oct. 22, 2014) Feast your eyes on this gorgeous family-friendly resort. Video provided by Working Mother
Powered by NewsLook.com
What Your Favorite Color Says About You

What Your Favorite Color Says About You

Buzz60 (Oct. 22, 2014) We all have one color we love to wear, and believe it or not, your color preference may reveal some of your character traits. In celebration of National Color Day, Krystin Goodwin (@kyrstingoodwin) highlights what your favorite colors may say about you. Video provided by Buzz60
Powered by NewsLook.com
First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

Newsy (Oct. 21, 2014) A medical team has for the first time given a man the ability to walk again after transplanting cells from his brain onto his severed spinal cord. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins