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Scientists zero in on enzyme at work in Alzheimer's disease

February 26, 2001

NIA Press Office | 301-496-1752 | nianews3@mail.nih.gov

Experiments in a newly developed mouse model to determine which of two beta secretases in the brain might be principally responsible for developing the destructive plaques of Alzheimer's disease (AD) provide new evidence that the culprit is BACE1, a recently identified enzyme. According to this latest report, BACE1 begins the process that cleaves, or snips, a protein in the brain, forming beta amyloid protein fragments that come together to make AD plaques. The intensifying focus on BACE1 has important implications for treatment of people with AD, suggesting that a drug could be developed to inactivate BACE1 to prevent the buildup of beta amyloid in the human brain.

The findings are described in the March 2001 issue of Nature Neuroscience . The research is reported by Philip C. Wong, Ph.D., Huaibin Cai, Ph.D., Donald Price, Ph.D., and their colleagues at The Johns Hopkins University School of Medicine, joined by scientists at Ciphergen Biosystems, Inc., Fremont, CA. The National Institute on Aging (NIA), the Adler Foundation, and the Bristol-Myers Squibb Foundation supported the research.

AD is caused by a complex cascade of events taking place over many years inside the brain. A major focus of study has been the process by which beta amyloid accumulates in the brain to form the plaques, which interfere with communications among neurons, or brain cells. One intense area of research, addressed in today's findings, examines how a brain protein, the amyloid precursor protein (APP), is cleaved by enzymes to release beta amyloid fragments.

Previous work had demonstrated that the BACE1 enzyme was likely responsible for cleaving one end of the beta amyloid fragment from APP. However, there remained the possibility that another enzyme, BACE2, was also involved. This new finding shows that BACE1 is indeed the major player in neurons.

"This study marks another important step in our understanding of the etiology of AD, of how abnormal proteins are processed in the brain as the disease develops," says Creighton H. Phelps, Ph.D., director of the NIA's Alzheimer's Disease Centers Program. "Further research is needed to determine the relationship between the deposition of amyloid and changes in brain function. But with information such as this, we are one step closer to defining targets for treatment that might prevent the deposition of toxic beta amyloid in the brain." Scientists are hoping that preventing or reducing buildup of beta amyloid plaques will prevent clinical signs of the disease, such as loss of cognitive function and memory, in patients.

In order to understand the relative importance in the brain of the two beta secretases, BACE1 and BACE2, known to cleave APP, the scientists developed a "knockout" mouse in which the gene for the BACE1 enzyme was eliminated to see whether removing the enzyme would interfere with the production of beta amyloid. With the enzyme gone, beta amyloid peptides were no longer produced in neuronal cultures from the knockout mice. Scientists then concluded that the BACE1 was involved in the amyloid-producing activity, and BACE2 appeared to play a much smaller role in the cleavage of APP in neurons.

The scientists also looked at the role of BACE1versus that of alpha secretase, an enzyme involved in normal, nonpathological processing of APP into soluble products. They found that the two enzymes appear to compete with each other in the processing of APP, further demonstrating that BACE1 is the primary APP-cleaving enzyme.

In addition, the scientists looked for but did not find any major changes in the brains of the test mice when compared with controls from the same litter. This finding provides some preliminary evidence that major adverse effects might possibly be avoided in therapies using BACE1 inhibitors. Scientists say they now need to follow the mice over a longer period of time to examine the influence that lack of the BACE1 enzyme might have beyond the six months observed so far.

Johns Hopkins University is one of 30 Alzheimer's Disease Centers around the U.S. supported by the NIA. The NIA leads the federal effort to understand AD and to develop ways to treat or prevent the disease, and much of the work in this area takes place at the AD centers.

The NIA also sponsors a web site dedicated to information on AD and memory, which is located at www.nia.nih.gov/alzheimers/. The site is run by NIA's Alzheimer's Disease Education and Referral (ADEAR) Center, which can also be contacted by calling 1-800-438-4380. For general information on aging, visit the NIA web site at www.nia.nih.gov, or call 1-800-222-2225.

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