Naturally occurring enzyme can break down key part of Alzheimer's plaques

October 24, 2006

Scientists have identified a naturally occurring enzyme that can break down a key component of the brain plaques characteristic of Alzheimer's disease. The finding may provide researchers with new opportunities to understand what goes wrong in the brains of Alzheimer's patients and could one day help them seek new therapies.

Researchers at Washington University School of Medicine in St. Louis showed earlier this summer that the enzyme, matrix metalloproteinase 9 (MMP-9), degrades abnormally aggregated proteins known as amyloid fibrils, a main ingredient of brain plaques. In the brain, MMP-9 is made by support cells known as astrocytes.

MMP-9 is already well-known because of its links to cancer metastases, vascular disease, arthritis and other pathologies. Scientists called the new link to Alzheimer's encouraging, noting that previously identified enzymes only degrade a smaller, nonaggregated component of Alzheimer's plaques.

"We already knew of three enzymes that break down amyloid beta (Abeta), a protein fragment that clumps together with itself to form the fibrils," says Jin-Moo Lee, M.D., Ph.D., assistant professor of neurology. "But the thinking up until now had been that Abeta might be clumping together so tightly that the fibrils were indestructible."

In a new study, appearing October 25 in The Journal of Neuroscience, Lee's group found that disabling the mouse gene for MMP-9 increased levels of Abeta in the spaces between brain cells. The finding proves that MMP-9 contributes to clearance of Abeta from extracellular spaces and suggests its dysfunction could potentially contribute to the development of Alzheimer's.

"MMP-9 and other enzymes like it are secreted from brain support cells and active in the spaces outside of cells, and that's where we saw an increase in Abeta levels in the mice that lacked the gene for MMP-9," Lee notes. "That's relevant to Alzheimer's because all the amyloid plaques are extracellular, and the formation of the plaques seems to be related to an elevated level of Abeta that accumulates over time in those spaces."

In earlier studies, Lee's lab analyzed the production of MMP-9 in astrocytes. They found astrocytes close to amyloid plaques increased their MMP-9 production. Imaging studies also showed that MMP-9 levels increased around blood vessels laden with amyloid.

"Astrocytes become activated around plaques as they develop, and then eventually form a wall surrounding the plaques," he says.

Lee's results have led him to formulate a provocative but as yet unproven theory about an old mystery of Alzheimer's disease: why plaques continue to increase in number over time but only grow to a certain size.

"Even though everything we know about the fibrils suggests they should constantly grow, plaques reach a mature size and stop growing," Lee says. "It's possible that production of MMP-9 and other similar substances by support cells in the brain is establishing a balance that prevents the plaques from growing beyond a certain size."

To follow up, Lee plans to crossbreed mice lacking MMP-9 with a line of mice genetically modified to develop an Alzheimer's-like condition. Scientists want to see if removing MMP-9 causes the mice to develop Alzheimer's more quickly.

In a parallel project that will test MMP-9's potential as a therapeutic, Lee and his collaborators will use viruses to alter production of MMP-9 in the mouse model. Researchers want to learn if increasing levels of the enzyme present in the brain can delay onset of Alzheimer's.

Source: Washington University School of Medicine, By Michael Purdy

Related Stories

Recommended for you

Groundbreaking investigative effort identifies gonorrhea vaccine candidates

September 19, 2017
Researchers at Oregon State University have identified a pair of proteins that show promise as the basis for a gonorrhea vaccine.

Snail fever progression linked to nitric oxide production

September 14, 2017
Bilharzia, caused by a parasitic worm found in freshwater called Schistosoma, infects around 200 million people globally and its advance can lead to death, especially in children in developing countries.

Systems analysis points to links between Toxoplasma infection and common brain diseases

September 13, 2017
More than 2 billion people - nearly one out of every three humans on earth, including about 60 million people in the United States - have a lifelong infection with the brain-dwelling parasite Toxoplasma gondii.

Study clears important hurdle toward developing an HIV vaccine

September 13, 2017
An international team of researchers has demonstrated a way of overcoming one of the major stumbling blocks that has prevented the development of a vaccine against HIV: the ability to generate immune cells that stay in circulation ...

As 'flesh-eating' Leishmania come closer, a vaccine against them does, too

September 13, 2017
Parasites that ulcerate the skin, can disfigure the face, and may fatally mutilate its victim's internal organs are creeping closer to the southern edges of the United States.

Promising clinical trial results could give doctors a new tool against drug-resistant strains of malaria parasite

September 13, 2017
Tulane University researchers have developed a new drug that is effective against non-severe cases of malaria, according to results from an FDA-supervised clinical trial published in the latest issue of The Lancet Infectious ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.