Hopkins scientists show enzyme is key to hallmark of Alzheimer's

November 05, 2000

Scientists at Johns Hopkins have demonstrated that a specific enzyme in the brain is essential for nerve cells to form a hallmark of Alzheimer's disease (AD) - the so-called amyloid plaques that collect and surround brain cells. While aging brains of apparently healthy people contain scattered amyloid plaques, the brains of AD patients are littered with them.

Last year, five research groups cloned the gene for the enzyme, called beta-secretase, but the Hopkins scientists say they are the first to show the enzyme is responsible for forming the molecules that comprise plaque within the brain's nerve cells. Beta amyloid - the plaque molecule - forms inside nerve cells, then is shuttled outside where it collects into plaques.

Beta-secretase is a topic of intense research interest for pharmaceutical and academic centers worldwide because it's one of two enzymes associated with plaque formation. Many scientists believe plaques are the probable trigger of AD's destruction in the brain. "Knowing this enzyme is the major player in forming plaques offers a way to tell if the structures truly are important in Alzheimer's. And if that's the case, the enzyme also offers a clear target for therapy," says research team member Philip Wong, Ph.D.

The research is scheduled for presentation at this year's meetings of the Society for Neuroscience in New Orleans.

In the Hopkins study, scientists knocked out the genes for beta-secretase in mice. They then cultured nerve cells from the animals' brains and, using antibodies targeted to beta-secretase, confirmed the enzyme wasn't present. As expected, the nerve cells lacking the enzyme failed to form beta amyloid, the plaque protein.

"The mice without beta-secretase genes are born apparently normal and seem to suffer no untoward effects, but we're watching the mice as they age," says Huaibin Cai, Ph.D., another of the researchers. "So far, at four months, the mice appear fine."

"We're really encouraged by possible therapeutic implications," says Wong, "because scientists are already designing small molecules capable of crossing the brain's blood-brain barrier." The molecules could, in theory, be fine-tuned to inhibit such enzymes as beta-secretase, Wong adds, which could squelch plaque production.

Last year, other researchers reported preventing plaque production in mice by immunizing the animals against their own plaque protein. "Both approaches may prove useful in treating Alzheimer's," Wong explains.

Beta-secretase works by trimming pieces off a larger molecule that's parent to the plaque protein, beta amyloid. Forming amyloid is a natural cell process, says Wong. It's part of a poorly understood event in cells where amyloid appears and then is cleared. "But in Alzheimer's," he explains, "something goes wrong and amyloid really increases."

A current hypothesis of AD is that as amyloid builds up, nerve cells are damaged and brain tissues become inflamed. Some researchers believe this chronic inflammation progressively injures nerve cells, leading to the symptoms of the disease.

Scientists say another enzyme, called gamma-secretase, is also involved in brain production of plaque. However, the Hopkins researchers say, the nature of gamma-secretase remains controversial.

Gamma-secretase is a research hot spot because nearly a quarter of the people with early-onset Alzheimer's have mutations in genes (presenilin genes) linked with the enzyme's activity.
-end-
This study was funded by grants from the National Institutes of Health, Bristol-Myers Squibb Foundation and the Adler Foundation.

Other members of the research team were Yanshu Wang, Ph.D., Diane McCarthy, Ph.D., Hongjin Wen, M.S., David R. Borschelt, Ph.D., and Donald L. Price, M.D.

This paper will be presented Monday, Nov. 6 at the poster session at 11 a.m., section NN-70, room 276, Hall G-H, of the Morial Convention Center.

Related Web site: For more information on the work of the Hopkins pathology lab:
http://162.129.103.69/MCGI/SEND^WEBUTLTY(1058)/893886796

Johns Hopkins Medical Institutions' news releases are available on an EMBARGOED basis on EurekAlert at http://www.eurekalert.org, Newswise at http://www.newswise.com and from the Office of Communications and Public Affairs' direct e-mail news release service. To enroll, call 410-955-4288 or send e-mail to bsimpkins@jhmi.edu.

On a POST-EMBARGOED basis find them at http://hopkins.med.jhu.edu, Quadnet at http://www.quad-net.com and ScienceDaily at http://www.sciencedaily.com.

Media Contact: Marjorie Centofanti 410-955-8725
Email: mcentofanti@jhmi.edu

During the meeting, you can reach Marjorie by cell phone at 410-693-2550 (11/3-11/8).

Johns Hopkins Medicine

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