Featured Research

from universities, journals, and other organizations

Right target, but missing the bulls-eye for Alzheimer's

Date:
January 23, 2013
Source:
University of California, Los Angeles (UCLA), Health Sciences
Summary:
For decades now, researchers have been trying, without success, to develop drugs that slow or prevent Alzheimer’s. Now research at suggests that while the protein they have been focusing on-- amyloid-beta -- is the right one, what’s needed is to direct a drug to a very specific location, which they’ve discovered, on that protein.

Alzheimer's disease is the most common cause of late-life dementia. The disorder is thought to be caused by a protein known as the amyloid-beta protein, or Abeta, which clumps together in the brain, forming plaques that are thought to destroy neurons. This destruction starts early, too, and can presage clinical signs of the disease by up to 20 years.

Related Articles


For decades now, researchers have been trying, with limited success, to develop drugs that prevent this clumping. Such drugs require a "target" -- a structure they can bind to, thereby preventing the toxic actions of Abeta.

Now, a new study out of UCLA suggests that while researchers may have the right target in Abeta, they may be missing the bull's-eye. Reporting in the Jan. 23 issue of the Journal of Molecular Biology, UCLA neurology professor David Teplow and colleagues focused on a particular segment of a toxic form of Abeta and discovered a unique hairpin-like structure that facilitates clumping.

"Every 68 seconds, someone in this country is diagnosed with Alzheimer's," said Teplow, the study's senior author and principal investigator of the NIH-sponsored Alzheimer's Disease Research Center at UCLA. "Alzheimer's disease is the only one of the top 10 causes of death in America that cannot be prevented, cured or even slowed down once it begins. Most of the drugs that have been developed have either failed or only provide modest improvement of the symptoms. So finding a better pathway for these potential therapeutics is critical."

The Abeta protein is composed of a sequence of amino acids, much like "a pearl necklace composed of 20 different combinations of different colors of pearl," Teplow said. One form of Abeta, Abeta40, has 40 amino acids, while a second form, Abeta42, has two extra amino acids at one end. Abeta42 has long been thought to be the toxic form of Abeta, but until now, no one has understood how the simple addition of two amino acids made it so much more toxic then Abeta40.

In his lab, Teplow and his colleagues used computer simulations in which they looked at the structure of the Abeta proteins in a virtual world. The researchers first created a virtual Abeta peptide that only contained the last 12 amino acids of the entire 42-amino-acid-long Abeta42 protein. Then, said Teplow, "we just let the molecule move around in a virtual world, letting the laws of physics determine how each atom of the peptide was attracted to or repulsed by other atoms."

By taking thousands of snapshots of the various molecular structures the peptides created, the researchers determined which structures formed more frequently than others. From those, they then physically created mutant Abeta peptides using chemical synthesis.

"We studied these mutant peptides and found that the structure that made Abeta42 Abeta42 was a hairpin-like turn at the very end of the peptide of the whole Abeta protein," Teplow said.

The hairpin turn structure was not previously known in the detail revealed by the researchers, "so we feel our experiments were novel," he said. "Our lab is the first to show that it is this specific turn that accounts for the special ability of Abeta42 to aggregate into clumps that we think kills neurons. Abeta40, the Abeta protein with two less amino acids at the end of the protein, did not do the same thing."

Hopefully, the work of the Teplow laboratory presents what may the most relevant target yet for the development of drugs to fight Alzheimer's disease, the researchers said.

Other authors on the study included Robin Roychaudhuri, Mingfeng Yang, Atul Deshpande, Gregory M. Cole and Sally Frautschy, all of UCLA, and Aleksey Lomakin and George B. Benedek of the Massachusetts Institute of Technology.

Funding for the study was provided by grants from the State of California Alzheimer's Disease Research Fund, a UCLA Faculty Research Grant, the National Institutes of Health (AG027818, NS038328) and the James Easton Consortium for Alzheimer's Drug Discovery and Biomarkers.


Story Source:

The above story is based on materials provided by University of California, Los Angeles (UCLA), Health Sciences. Note: Materials may be edited for content and length.


Journal Reference:

  1. Robin Roychaudhuri, Mingfeng Yang, Atul Deshpande, Gregory M. Cole, Sally Frautschy, Aleksey Lomakin, George B. Benedek, David B. Teplow. C-Terminal Turn Stability Determines Assembly Differences between Aβ40 and Aβ42. Journal of Molecular Biology, 2013; 425 (2): 292 DOI: 10.1016/j.jmb.2012.11.006

Cite This Page:

University of California, Los Angeles (UCLA), Health Sciences. "Right target, but missing the bulls-eye for Alzheimer's." ScienceDaily. ScienceDaily, 23 January 2013. <www.sciencedaily.com/releases/2013/01/130123221409.htm>.
University of California, Los Angeles (UCLA), Health Sciences. (2013, January 23). Right target, but missing the bulls-eye for Alzheimer's. ScienceDaily. Retrieved October 24, 2014 from www.sciencedaily.com/releases/2013/01/130123221409.htm
University of California, Los Angeles (UCLA), Health Sciences. "Right target, but missing the bulls-eye for Alzheimer's." ScienceDaily. www.sciencedaily.com/releases/2013/01/130123221409.htm (accessed October 24, 2014).

Share This



More Health & Medicine News

Friday, October 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

IKEA Desk Converts From Standing to Sitting With One Button

IKEA Desk Converts From Standing to Sitting With One Button

Buzz60 (Oct. 24, 2014) IKEA is out with a new convertible desk that can convert from a sitting desk to a standing one with just the push of a button. Jen Markham explains. Video provided by Buzz60
Powered by NewsLook.com
Ebola Protective Suits Being Made in China

Ebola Protective Suits Being Made in China

AFP (Oct. 24, 2014) A factory in China is busy making Ebola protective suits for healthcare workers and others fighting the spread of the virus. Duration: 00:38 Video provided by AFP
Powered by NewsLook.com
WHO: Millions of Ebola Vaccine Doses by 2015

WHO: Millions of Ebola Vaccine Doses by 2015

AP (Oct. 24, 2014) The World Health Organization said on Friday that millions of doses of two experimental Ebola vaccines could be ready for use in 2015 and five more experimental vaccines would start being tested in March. (Oct. 24) Video provided by AP
Powered by NewsLook.com
Doctor in NYC Quarantined With Ebola

Doctor in NYC Quarantined With Ebola

AP (Oct. 24, 2014) An emergency room doctor who recently returned to the city after treating Ebola patients in West Africa has tested positive for the virus. He's quarantined in a hospital. (Oct. 24) Video provided by AP
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