Featured Research

from universities, journals, and other organizations

Promising new drug target for Alzheimer's disease

Date:
April 20, 2010
Source:
University of Illinois at Urbana-Champaign
Summary:
Researchers have identified a potential drug target for the treatment of Alzheimer's disease: a receptor that is embedded in the membrane of neurons and other cells. A protein fragment associated with Alzheimer's disease activates this receptor, sparking increased activity in the affected neurons, eventually leading to cell death, researchers report.

The beta-2 adrenergic receptor (green) spans the cell membrane (orange and blue). In this visualization, a binding pocket in the receptor interacts with a beta-blocker (red, gray and blue molecule near the center). The new study found that amyloid-beta, a protein fragment linked to the detrimental effects of Alzheimer's disease, binds to a different region on the beta-2 adrenergic receptor.
Credit: Public domain image from Wikimedia

Researchers at the University of Illinois have identified a potential drug target for the treatment of Alzheimer's disease: a receptor that is embedded in the membrane of neurons and other cells.

A protein fragment associated with Alzheimer's disease activates this receptor, sparking increased activity in the affected neurons, eventually leading to cell death, the researchers report. The new findings appear in the FASEB Journal.

Scientists have known for decades that a protein fragment, called amyloid-beta (AM-uh-loyd BAIT-uh), is a key to the riddle of Alzheimer's disease. Alois Alzheimer himself first found aggregates of this "peculiar substance" in the brain of a dementia patient after her death. These bundles of protein, or plaques, are composed almost entirely of amyloid-beta, and still are used to diagnose Alzheimer's disease after death.

Animals with amyloid plaques in the brain experience a decline in brain function that mirrors that of Alzheimer's disease. A recent study found that neurons closest to these plaques tend to be hyperexcitable relative to normal, while activity in the surrounding neurons is depressed, indicating an imbalance in brain activity associated with these plaques.

Other studies have found that clumps of only two, or a few, amyloid-beta fragments somehow stimulate a receptor, called the AMPA receptor. When amyloid-beta binds to a neuron, the AMPA receptor opens a channel that lets calcium or sodium ions into the cell.

Normally the AMPA receptor opens this channel only when it binds to glutamate, a potent neurotransmitter that is important to normal brain function as well as memory and learning. In either case, the quick influx of ions causes a nerve impulse.

To date, scientists have not been able to identify a mechanism by which amyloid-beta causes the AMPA receptor channel to open, however.

"If a mouse is exposed to amyloid-beta in the brain, it impairs neuron function, causing memory deficits and behavioral deficits," said Kevin Xiang, a professor of molecular and integrative physiology at Illinois who led the new study with professor Charles Cox and postdoctoral fellows Dayong Wang and Govindaiah in the same department. "The question is how this peptide causes all these detrimental cellular effects."

For the new study, the researchers focused on the beta-2 adrenergic receptor, a protein that -- like the AMPA receptor -- resides in the cell membrane. Neurotransmitters and hormones normally activate the beta-2 adrenergic receptor, but amyloid-beta also induces a cascade of events in the neuron by activating the beta-2 adrenergic receptor, the researchers found. One of the downstream effects of this interaction is activation of the AMPA receptor ion channels. (In mice lacking the beta-2 adrenergic receptor, amyloid-beta had no discernible effect on AMPA receptors, they found.)

"We showed that we needed the presence of beta-2 adrenergic receptors to get the increase in the AMPA-mediated response," Cox said.

Further experiments showed that amyloid-beta does bind to the beta-2 adrenergic receptor.

Previous studies had found that blocking the AMPA receptor could alleviate the misfiring caused by amyloid plaques in the brain. But the AMPA receptor, which responds to glutamate, is important to learning and memory, so blocking it could also do harm, the researchers said.

"Glutamate is such a ubiquitous neurotransmitter throughout the brain, you can't simply go in and block its actions because if you do, you can just start rounding up the side effects," Cox said.

"Once you block the AMPA receptor you're basically dampening widespread neuronal excitability throughout the whole brain," Cox said. "Now we have something a bit more specific to latch onto: the beta-2 adrenergic receptor."

This receptor offers an attractive alternative target because, the researchers found, amyloid-beta binds to a different part of the receptor than that normally engaged by neurotransmitters and hormones. This means it may be possible to stop amyloid-beta from binding to it without hindering the other functions of the beta-2 adrenergic receptor.

Previous studies have shown that Alzheimer's patients who also take beta-blockers tend to see a slower decline in their mental function. These drugs are meant to treat hypertension and other conditions by targeting beta-adrenergic receptors, including beta-2. This finding provides further support to the idea that the beta-2 adrenergic receptor is a key to the ill effects of Alzheimer's disease.

Xiang and Cox stress that the beta-2 adrenergic receptor is almost certainly not the only important player in the damage that occurs in an Alzheimer's-afflicted brain. But they see it as a promising new potential target for future drug research.

Xiang and Cox are also professors in the Neuroscience Program. Cox is the head of the Department of Pharmacology in the College of Medicine, and a full-time member of the Beckman Institute and of the Center for Biophysics and Computational Biology at Illinois.

Partial funding for this study was provided by the National Institutes of Health.


Story Source:

The above story is based on materials provided by University of Illinois at Urbana-Champaign. Note: Materials may be edited for content and length.


Journal Reference:

  1. D. Wang, G. Govindaiah, R. Liu, V. De Arcangelis, C. L. Cox, Y. K. Xiang. Binding of amyloid peptide to 2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity. The FASEB Journal, 2010; DOI: 10.1096/fj.10-156661

Cite This Page:

University of Illinois at Urbana-Champaign. "Promising new drug target for Alzheimer's disease." ScienceDaily. ScienceDaily, 20 April 2010. <www.sciencedaily.com/releases/2010/04/100420114236.htm>.
University of Illinois at Urbana-Champaign. (2010, April 20). Promising new drug target for Alzheimer's disease. ScienceDaily. Retrieved August 22, 2014 from www.sciencedaily.com/releases/2010/04/100420114236.htm
University of Illinois at Urbana-Champaign. "Promising new drug target for Alzheimer's disease." ScienceDaily. www.sciencedaily.com/releases/2010/04/100420114236.htm (accessed August 22, 2014).

Share This




More Mind & Brain News

Friday, August 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Lost Brain Cells To Blame For Sleep Problems Among Seniors

Lost Brain Cells To Blame For Sleep Problems Among Seniors

Newsy (Aug. 21, 2014) According to a new study, elderly people might have trouble sleeping because of the loss of a certain group of neurons in the brain. Video provided by Newsy
Powered by NewsLook.com
Do More Wedding Guests Make A Happier Marriage?

Do More Wedding Guests Make A Happier Marriage?

Newsy (Aug. 20, 2014) A new study found couples who had at least 150 guests at their weddings were more likely to report being happy in their marriages. Video provided by Newsy
Powered by NewsLook.com
Charter Schools Alter Post-Katrina Landscape

Charter Schools Alter Post-Katrina Landscape

AP (Aug. 20, 2014) Nine years after Hurricane Katrina, charter schools are the new reality of public education in New Orleans. The state of Louisiana took over most of the city's public schools after the killer storm in 2005. (Aug. 20) Video provided by AP
Powered by NewsLook.com
Researcher Testing on-Field Concussion Scanners

Researcher Testing on-Field Concussion Scanners

AP (Aug. 19, 2014) Four Texas high school football programs are trying out an experimental system designed to diagnose concussions on the field. The technology is in response to growing concern over head trauma in America's most watched sport. (Aug. 19) 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