Featured Research

from universities, journals, and other organizations

Scientists identify protein that spurs formation of Alzheimer's plaques

Date:
September 2, 2010
Source:
Rockefeller University
Summary:
In Alzheimer's disease, the problem is beta-amyloid, a protein that accumulates in the brain and causes nerve cells to weaken and die. Drugs designed to eliminate plaques made of beta-amyloid have a fatal problem: they need to enter the brain and remove the plaques without attacking healthy brain cells. New research, however, suggests that treatments modeled on the blockbuster cancer drug Gleevec could be the solution.

In Alzheimer’s disease, amyloid plaques (dark spots) are the hallmark of the disorder. When scientists knocked out the gene that produces GSAP in a mouse model of the disease (bottom), the mice developed fewer amyloid plaques.
Credit: Image courtesy of Rockefeller University

In Alzheimer's disease, the problem is beta-amyloid, a protein that accumulates in the brain and causes nerve cells to weaken and die. Drugs designed to eliminate plaques made of beta-amyloid have a fatal problem: they need to enter the brain and remove the plaques without attacking healthy brain cells. New research from the laboratory of Nobel Prize winner Paul Greengard, however, suggests that treatments modeled on the blockbuster cancer drug Gleevec could be the solution.

The findings are reported in the Sept. 2 issue of the journal Nature.

Gleevec, it turns out, has the unique ability to bind to a protein that triggers the production of beta-amyloid plaques. The new research from Greengard's lab shows that this protein, called gamma-secretase activating protein (GSAP), dramatically and selectively increases the production of beta-amyloid peptide, which makes up the senile plaques found in the brains of most people with Alzheimer's. GSAP works through a mechanism involving its interactions with gamma-secretase, an enzyme that chops up the amyloid precursor protein, a large molecule produced naturally in the body and found in many different types of cells.

"Alzheimer's disease is a devastating disorder for which there are no satisfactory treatments," says Greengard, Vincent Astor Professor and director of the Fisher Center for Alzheimer's Research at Rockefeller. "Our findings reveal that gamma-secretase activating protein is a potential target for a new class of anti-amyloid therapies." Greengard won the 2000 Nobel Prize in Physiology or Medicine for research into how neurons communicate.

Scientists have been searching for ways to reduce beta-amyloid production in Alzheimer's patients by blocking gamma-secretase, but most gamma-secretase inhibitors also block the cleavage of an important immune system molecule called Notch. Notch plays a pivotal role in the development of blood-forming organs and the immune system. Earlier research by Greengard and his colleagues showed that Gleevec, a drug used to treat leukemia and gastrointestinal stromal tumors, successfully inhibited the ability of gamma secretase to form beta amyloid without affecting the Notch pathway.

In the new study, led by Gen He, a research associate in Greengard's lab, the researchers showed that GSAP stimulates production of beta-amyloid in cell lines, and that reducing GSAP reduces beta-amyloid. The researchers also looked at GSAP's action in a mouse model of Alzheimer's disease. They knocked down the gene that codes for GSAP using RNA interference, and found that levels of beta-amyloid as well as plaque development decreased. Biochemical studies showed that Gleevec reduces beta-amyloid production by binding to GSAP and preventing its activation of gamma-secretase.

Unfortunately, the Gleevec molecule does not cross the blood-brain barrier, the gatekeeper that prevents some substances in the blood from entering the brain. Greengard, however, believes that it will be possible to design drugs that target GSAP but do not have this limitation.

"Anti-amyloid therapeutic drugs represent a valid approach to treating Alzheimer's disease, but their inability to accumulate in the brain has limited their usefulness," says Greengard, who is head of the Laboratory of Molecular and Cellular Neuroscience. "The development of compounds that work like Gleevec, but have the ability to pass the blood-brain barrier and target GSAP could revolutionize the treatment of this disease."

This research was supported in part by grants from the National Institute of Aging, part of the federal government's National Institutes of Health, the U.S. Department of Defense, the Fisher Center for Alzheimer's Research Foundation and the F. M. Kirby Foundation. Additional funding was provided by Intracellular Therapies, Inc.


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. Gen He, Wenjie Luo, Peng Li, Christine Remmers, William J. Netzer, Joseph Hendrick, Karima Bettayeb, Marc Flajolet, Fred Gorelick, Lawrence P. Wennogle, Paul Greengard. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature, 2010; 467 (7311): 95 DOI: 10.1038/nature09325

Cite This Page:

Rockefeller University. "Scientists identify protein that spurs formation of Alzheimer's plaques." ScienceDaily. ScienceDaily, 2 September 2010. <www.sciencedaily.com/releases/2010/09/100901132144.htm>.
Rockefeller University. (2010, September 2). Scientists identify protein that spurs formation of Alzheimer's plaques. ScienceDaily. Retrieved September 21, 2014 from www.sciencedaily.com/releases/2010/09/100901132144.htm
Rockefeller University. "Scientists identify protein that spurs formation of Alzheimer's plaques." ScienceDaily. www.sciencedaily.com/releases/2010/09/100901132144.htm (accessed September 21, 2014).

Share This



More Mind & Brain News

Sunday, September 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Could Grief Affect The Immune Systems Of Senior Citizens?

Could Grief Affect The Immune Systems Of Senior Citizens?

Newsy (Sep. 19, 2014) The study found elderly people are much more likely to become susceptible to infection than younger adults going though a similar situation. Video provided by Newsy
Powered by NewsLook.com
Food Addiction Might Be Caused By PTSD

Food Addiction Might Be Caused By PTSD

Newsy (Sep. 18, 2014) New research shows that women who suffer from PTSD are three times more likely to develop a food addiction. Video provided by Newsy
Powered by NewsLook.com
Corporal Punishment on Decline, Debate Renews

Corporal Punishment on Decline, Debate Renews

AP (Sep. 16, 2014) Corporal punishment in the United States is on the decline, but there is renewed debate over its use after Minnesota Vikings running back Adrian Peterson was charged with child abuse. (Sept. 16) Video provided by AP
Powered by NewsLook.com
FDA Eyes Skin Shocks Used at Mass. School

FDA Eyes Skin Shocks Used at Mass. School

AP (Sep. 15, 2014) The FDA is considering whether to ban devices used by the Judge Rotenberg Educational Center in Canton, Massachusetts, the only place in the country known to use electrical skin shocks as aversive conditioning for aggressive patients. (Sept. 15) 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:
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