Featured Research

from universities, journals, and other organizations

Atomic Force Microscopy Used To Discover Effects Of Experimental Drugs On Alzheimer's Plaques

Date:
January 21, 2004
Source:
Carnegie Mellon University
Summary:
Scientists at Carnegie Mellon University have used atomic force microscopy (AFM) to shed light on molecular scale processes underlying the formation of insoluble plaques associated with Alzheimer's Disease. Results of this work suggest that AFM could lead to a better understanding of the disease process and help guide the search for new diagnostic and treatment approaches.

PITTSBURGH - Scientists at Carnegie Mellon University have used atomic force microscopy (AFM) to shed light on molecular scale processes underlying the formation of insoluble plaques associated with Alzheimer's Disease. Results of this work suggest that AFM could lead to a better understanding of the disease process and help guide the search for new diagnostic and treatment approaches. The report will be published in the Jan. 23 issue of the Journal of Molecular Biology and appears online at http://www.sciencedirect.com/web-editions/journal/00222836.

Related Articles


Supported by the National Institutes of Health, the research was done in collaboration with scientists at Eli Lilly and Company and the Washington University School of Medicine. "Because AFM provides three-dimensional topographical information at the nanoscale, it could prove important in assessing the potential usefulness of molecules like antibodies to effectively inhibit protein aggregation associated with Alzheimer's Disease," said Tomasz Kowalewski, Ph.D., assistant professor of chemistry at Carnegie Mellon and senior author on the paper.

Alzheimer's Disease belongs to a class of disorders called conformational diseases, which are caused by changes in a protein's physical state. Another widely known example is prion-based 'Mad Cow' disease. Tools used to understand these disorders are targeted primarily to biochemical processes, noted Kowalewski, who works at the Mellon College of Science. "Because AFM probes the physical state of proteins, it could really assist in understanding conformational diseases, which traditionally have been difficult to fight," said Kowalewski.

A hallmark of Alzheimer's Disease is the presence of insoluble plaques in the brains of disease victims. These plaques are made of beta amyloid (A฿), a peptide derived from a precursor protein found in cell membranes. Once cleaved from its parent protein, the A฿ peptide readily aggregates into fibrils that are rich in insoluble stacked structures called beta sheets.

These fibrils then congeal into tangled plaques. For the past few years, scientists in the field have been focusing considerable efforts on developing molecules that would inhibit A฿ aggregation or perhaps even break up existing plaques. In this quest, they have recently turned their attention to antibodies that bind to different portions of the A฿ peptide.

In their study, Kowalewski and a graduate student, Justin Legleiter, incubated the A฿ peptide in solution with two different monoclonal antibodies: m3D6, which binds near one end of the peptide called the amino terminus, and m266.2, which binds to the peptide's central portion.

Over several days, the researchers placed drops of the sample solutions on mica sheets and observed the degree of protein aggregation using AFM. The m266.2 antibody proved much better than m3D6 at preventing the formation of amyloid fibrils.

"Interestingly, we found that both antibodies interfere with the formation of protofibrils, or fibril precursors," noted Kowalewski. "In solutions of A฿ alone, numerous protofibrils were present under our experimental conditions as early as the third day, whereas in the presence of m3D6 they grew at a slower rate. We found that m266.2 completely inhibited protofibril formation."

The scientists believe that the two antibodies differ in their ability to inhibit fibril formation due to the way they bind to the A฿ peptide. Binding at one end of A฿, m3D6 does not inhibit the formation of extended beta sheets, which are the major structural feature of mature fibrils. Because m266.2 binds to the center of A฿, it blocks the formation of these extended beta sheets, the investigators surmised.

In AFM, a tiny lever ending with an ultra-sharp tip is scanned across a surface from side-to-side and top-to-bottom, much as a cursor moves across a computer screen. A laser beam reflected off the lever's end monitors its vertical motion. Perturbation of the lever motion by nanoscale features of a sample's surface topography is used to reconstruct a detailed three-dimensional map of the surface. In the study, the research team used custom-written software to process and to analyze their AFM images.

AFM is an appealing tool, according to Kowalewski, because it provides three-dimensional nanoscale images and, unlike some other techniques, it does not require specialized preparation or contrasting agents that could introduce artifacts. In addition, it allows to study the samples in liquids, under nearly physiological conditions, according to Kowalewski, who is now pursuing this kind of AFM studies to understand the interaction of antibodies and lipoproteins, with the A฿ peptide.

Collaborating investigators include Dan L. Czilli, Bruce Gitter and Ronald B. DeMattos (Eli Lilly and Company) and David M. Holtzman (Washington University).


Story Source:

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


Cite This Page:

Carnegie Mellon University. "Atomic Force Microscopy Used To Discover Effects Of Experimental Drugs On Alzheimer's Plaques." ScienceDaily. ScienceDaily, 21 January 2004. <www.sciencedaily.com/releases/2004/01/040121080931.htm>.
Carnegie Mellon University. (2004, January 21). Atomic Force Microscopy Used To Discover Effects Of Experimental Drugs On Alzheimer's Plaques. ScienceDaily. Retrieved November 27, 2014 from www.sciencedaily.com/releases/2004/01/040121080931.htm
Carnegie Mellon University. "Atomic Force Microscopy Used To Discover Effects Of Experimental Drugs On Alzheimer's Plaques." ScienceDaily. www.sciencedaily.com/releases/2004/01/040121080931.htm (accessed November 27, 2014).

Share This


More From ScienceDaily



More Mind & Brain News

Thursday, November 27, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Are Female Bosses More Likely To Be Depressed?

Are Female Bosses More Likely To Be Depressed?

Newsy (Nov. 24, 2014) — A new study links greater authority with increased depressive symptoms among women in the workplace. Video provided by Newsy
Powered by NewsLook.com
Winter Can Cause Depression — Here's How To Combat It

Winter Can Cause Depression — Here's How To Combat It

Newsy (Nov. 23, 2014) — Millions of American suffer from seasonal depression every year. It can lead to adverse health effects, but there are ways to ease symptoms. Video provided by Newsy
Powered by NewsLook.com
Could Your Genes Be The Reason You're Single?

Could Your Genes Be The Reason You're Single?

Newsy (Nov. 21, 2014) — Researchers in Beijing discovered a gene called 5-HTA1, and carriers are reportedly 20 percent more likely to be single. Video provided by Newsy
Powered by NewsLook.com
Milestone Birthdays Can Bring Existential Crisis, Study Says

Milestone Birthdays Can Bring Existential Crisis, Study Says

Newsy (Nov. 21, 2014) — Researchers find that as people approach new decades in their lives they make bigger life decisions. 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