Featured Research

from universities, journals, and other organizations

Scientists ID compounds that target amyloid fibrils in Alzheimer's, other brain diseases

Date:
July 26, 2013
Source:
University of California - Los Angeles
Summary:
Scientists report an advance toward "structure-based drug design," with the potential to delay or treat Alzheimer's disease, Parkinson's disease, type II diabetes, ALS (also known as Lou Gehrig's disease) and many other degenerative diseases.

Small molecules binding to amyloid fibrils. The stacked gray arrows are an artistic representation of the amyloid proteins associated with numerous diseases, including Alzheimer's. When proteins enter amyloid, they stack up like the rungs of a ladder and interfere with normal operations of biological cells. The green and red molecules are atomic representations of one of the compounds discovered by Jiang, et al., which bind to amyloid fibers. Carbon atoms are colored green, oxygen atoms are red, and nitrogen atoms are blue.
Credit: Lin Jiang, David Eisenberg/UCLA, Howard Hughes Medical Institute

UCLA chemists and molecular biologists have for the first time used a "structure-based" approach to drug design to identify compounds with the potential to delay or treat Alzheimer's disease, and possibly Parkinson's, Lou Gehrig's disease and other degenerative disorders.

All of these diseases are marked by harmful, elongated, rope-like structures known as amyloid fibrils, linked protein molecules that form in the brains of patients.

Structure-based drug design, in which the physical structure of a targeted protein is used to help identify compounds that will interact with it, has already been used to generate therapeutic agents for a number of infectious and metabolic diseases.

The UCLA researchers, led by David Eisenberg, director of the UCLA-Department of Energy Institute of Genomics and Proteomics and a Howard Hughes Medical Institute investigator, report the first application of this technique in the search for molecular compounds that bind to and inhibit the activity of the amyloid-beta protein responsible for forming dangerous plaques in the brain of patients with Alzheimer's and other degenerative diseases.

In addition to Eisenberg, who is also a professor of chemistry, biochemistry and biological chemistry and a member of UCLA's California NanoSystems Institute, the team included lead author Lin Jiang, a UCLA postdoctoral scholar in Eisenberg's laboratory and Howard Hughes Medical Institute researcher, and other UCLA faculty.

The research was published July 16 in eLife, a new open-access science journal backed by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.

A number of non-structural screening attempts have been made to identify natural and synthetic compounds that might prevent the aggregation and toxicity of amyloid fibrils. Such studies have revealed that polyphenols, naturally occurring compounds found in green tea and in the spice turmeric, can inhibit the formation of amyloid fibrils. In addition, several dyes have been found to reduce amyloid's toxic effects, although significant side effects prevent them from being used as drugs.

Armed with a precise knowledge of the atomic structure of the amyloid-beta protein, Jiang, Eisenberg and colleagues conducted a computational screening of 18,000 compounds in search of those most likely to bind tightly and effectively to the protein.

Those compounds that showed the strongest potential for binding were then tested for their efficacy in blocking the aggregation of amyloid-beta and for their ability to protect mammalian cells grown in culture from the protein's toxic effects, which in the past has proved very difficult. Ultimately, the researchers identified eight compounds and three compound derivatives that had a significant effect.

While these compounds did not reduce the amount of protein aggregates, they were found to reduce the protein's toxicity and to increase the stability of amyloid fibrils -- a finding that lends further evidence to the theory that smaller assemblies of amyloid-beta known as oligomers, and not the fibrils themselves, are the toxic agents responsible for Alzheimer's symptoms.

The researchers hypothesize that by binding snugly to the protein, the compounds they identified may be preventing these smaller oligomers from breaking free of the amyloid-beta fibrils, thus keeping toxicity in check.

An estimated 5 million patients in the U.S. suffer from Alzheimer's disease, the most common form of dementia. Alzheimer's health care costs in have been estimated at $178 billion per year, including the value of unpaid care for patients provided by nearly 10 million family members and friends.

In addition to uncovering compounds with therapeutic potential for Alzheimer's disease, this research presents a new approach for identifying proteins that bind to amyloid fibrils -- an approach that could have broad applications for treating many diseases.

Co-authors on the research included Cong Liu, David Leibly, Meytal Landau, Minglei Zhao and Michael Hughes.

The research was funded by the Howard Hughes Medical Institute and the National Institute of Aging, part of the National Institutes of Health (grant AG-029430).


Story Source:

The above story is based on materials provided by University of California - Los Angeles. Note: Materials may be edited for content and length.


Journal Reference:

  1. L. Jiang, C. Liu, D. Leibly, M. Landau, M. Zhao, M. P. Hughes, D. S. Eisenberg. Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta. eLife, 2013; 2 (0): e00857 DOI: 10.7554/eLife.00857

Cite This Page:

University of California - Los Angeles. "Scientists ID compounds that target amyloid fibrils in Alzheimer's, other brain diseases." ScienceDaily. ScienceDaily, 26 July 2013. <www.sciencedaily.com/releases/2013/07/130726092429.htm>.
University of California - Los Angeles. (2013, July 26). Scientists ID compounds that target amyloid fibrils in Alzheimer's, other brain diseases. ScienceDaily. Retrieved April 17, 2014 from www.sciencedaily.com/releases/2013/07/130726092429.htm
University of California - Los Angeles. "Scientists ID compounds that target amyloid fibrils in Alzheimer's, other brain diseases." ScienceDaily. www.sciencedaily.com/releases/2013/07/130726092429.htm (accessed April 17, 2014).

Share This



More Mind & Brain News

Thursday, April 17, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Are School Dress Codes Too Strict?

Are School Dress Codes Too Strict?

AP (Apr. 16, 2014) Pushing the limits on style and self-expression is a rite of passage for teens and even younger kids. How far should schools go with their dress codes? The courts have sided with schools in an era when school safety is paramount. (April 16) Video provided by AP
Powered by NewsLook.com
Could Even Casual Marijuana Use Alter Your Brain?

Could Even Casual Marijuana Use Alter Your Brain?

Newsy (Apr. 16, 2014) A new study conducted by researchers at Northwestern and Harvard suggests even casual marijuana use can alter your brain. Video provided by Newsy
Powered by NewsLook.com
Couples Who Sleep Less Than An Inch Apart Might Be Happiest

Couples Who Sleep Less Than An Inch Apart Might Be Happiest

Newsy (Apr. 16, 2014) A new study by British researchers suggests couples' sleeping positions might reflect their happiness. Video provided by Newsy
Powered by NewsLook.com
Cognitive Function: Is It All Downhill From Age 24?

Cognitive Function: Is It All Downhill From Age 24?

Newsy (Apr. 15, 2014) A new study out of Canada says cognitive motor performance begins deteriorating around age 24. 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:
from the past week

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