Researchers from Massachusetts General Hospital (MGH) have found that the amount and activity of an enzyme associated with the creation of amyloid-beta protein, the sticky fragments making up the plaques found in the brains of people with Alzheimer's disease, are elevated in parts of the brain where those plaques most frequently occur. Levels of the beta-site APP-cleaving enzyme (BACE) were significantly higher in the temporal cortex and frontal cortex of brain tissue from patients with Alzheimer's disease than in control patients. BACE is also known as beta-secretase, one of two enzymes required to clip or cut the larger amyloid percursor protein (APP) into fragments that include amyloid-beta. The report, which appears in the September Archives of Neurology, may improve understanding of the most common form of Alzheimer's disease. "Our key finding is that beta-secretase activity, the efficiency of how the enzyme works, is increased in Alzheimer's diseased brains specifically in those areas affected by the disease," says Michael Irizarry, MD, of the Alzheimer's Disease Research Unit in the MGH Department of Neurology, the paper's senior author. "The beta-secretase increase persists and even increases throughout the duration of the illness, which may make this enzyme a useful target for treatment, even late in the disease."
In Alzheimer's, amyloid-beta is released when the large APP molecule is clipped in one location by beta-secretase and in another spot by an enzyme called gamma-secretase. The amyloid-beta fragments collect in plaques, one of the classic brain abnormalities of Alzheimer's disease, which significant evidence suggests are toxic to brain cells. Normal processing of APP by an enzyme called alpha-secretase produces an alternative, non-toxic protein.
To investigate why amyloid plaques appear in certain areas of the brain, Irizarry and his colleagues designed new assays to measure the quantity and function of BACE in brain tissue from 61 patients who had died with Alzheimer's disease and 33 age-matched controls who did not have Alzheimer's when they died. The researchers found that the activity of BACE was increased 63 percent in the temporal cortex of Alzheimer's patients compared with the controls, with greater increases seen in patients with longer-term disease. BACE activity was increased 13 percent in the frontal cortex of Alzheimer's patients, and amounts of the protein were similarly increased in the same brain areas. However, no increase in BACE protein or its activity was seen in the cerebellar cortex, a part of the brain in which amyloid plaques do not develop.
Irizarry and his colleagues also note that increased production of amyloid-beta protein by mutations in the genes for APP or gamma-secretase is an established mechanism of amyloid plaque formation in rare inherited forms of Alzheimer's disease. The current findings about BACE changes in the brains of patients with Alzheimer's disease provide compelling evidence that increased amyloid-beta production is also important in sporadic Alzheimer's disease, by far the most common form of the disease. The next step will be to investigate factors underlying the increased BACE activity in Alzheimer's brains.
Along with Irizarry, who is an assistant professor of Neurology at Harvard Medical School, the report's co-authors are Hiroaki Fukumoto, PhD, first author; Bonnie Cheung, BS; and Bradley Hyman, MD, PhD; all of the MGH Alzheimer's Disease Research Unit. The research was supported by grants from the National Institutes of Health, the Walters Family Foundation and Takeda Chemical Industries.
The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, neuroscience, transplantation biology and photomedicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.
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