March 25, 2003
Two new research findings suggest that boosting normal, protective processes in the brain might help degrade or prevent damaging protein plaques associated with Alzheimer's disease (AD). In one publication, researchers at The Salk Institute and colleagues at other institutions found that gene transfer of the enzyme neprilysin may help clear a protein that forms amyloid plaques in humans. The experiments -- in mice -- are an important step in the development of an alternative approach to controlling AD and suggest closer study of the potential for neprilysin therapy.
The findings, by Fred H. Gage, Robert A. Marr, and Inder M. Verma at The Salk Institute for Biological Studies, Eliezer Masliah at the University of California San Diego and Atish Mukherjee and Louis B. Hersh at the University of Kentucky, Lexington, are reported in the latest issue of The Journal of Neuroscience.*
The Gage report comes on the heels of another study, reported March 3, 2003, in the online version of Nature Medicine, by Jens Husemann, Columbia University, New York, Tony Wyss-Coray, Veterans Affairs Palo Alto Health Care System and Stanford University in California, and colleagues. Husemann's group found that certain cells in the brain, called astrocytes, can degrade the beta amyloid peptide in cell cultures. While not yet tested in an animal model, the study's finding that astrocytes can be effectively mobilized at the cellular level suggests yet another possible target for potential therapies for AD.
"In recent years, we have been looking at ways to battle amyloid," says Brad Wise, Program Director, Fundamental Neuroscience, the National Institute on Aging's (NIA) Neuroscience and Neuropsychology of Aging Program. "Most studies have focused on blocking the production of proteins that form AD plaques. Both of these studies suggest how we might clear amyloid even if it does build up in the brain. These are very new ways of addressing the problem."
The Gage research was funded by the NIA, part of the National Institutes of Health, U.S. Department of Health and Human Services. Funding was also provided by the Alzheimer's Association, the Canadian Institutes of Health Research, and other funds and foundations. The Husemann study was funded by the NIA and the Alzheimer's Association.
Scientists have known for many years that amyloid plaques in the brain are a hallmark feature of AD in humans. Studies on the etiology of the disease have shown that the plaques are formed when the larger amyloid precursor protein (APP) is broken up, resulting in the formation of beta amyloid protein fragments, or abeta peptides, that clump together to form insoluble amyloid plaques in certain areas of the brain with AD. It has been hypothesized that one approach to preventing AD or delaying its clinical symptoms might be to interfere with the production of beta amyloid or, more recently, to degrade beta amyloid or its plaques.
Previous research has shown that neprilysin is reduced in areas vulnerable to plaque formation and that mice without the neprilysin gene have increased levels of beta amyloid in the brain. Test tube studies have also shown that neprilysin could help stop the production of beta amyloid.
The current experiments reported by Gage and colleagues represent the first demonstration that increased levels of neprilysin decrease the deposition of amyloid in an animal model. In this study, the team injected gene vectors carrying human neprilysin into the amyloid-containing brains of transgenic mice. The gene transfer was concentrated in two areas of the brain, the hippocampus and the frontal cortex, both areas where plaque formation occurs in humans.
At the end of the treatment, the researchers reported, introduction of the neprilysin appeared to increase degradation or reduce the growth of already existing plaques. Plaques found in areas strongly "expressing" neprilysin, near the injection sites, were found to be smaller and more compact than in other regions of the brains. In some cases, what the researchers call plaque "load" was reduced to less than half that found in comparable, untreated areas. There was also evidence that neurodegeneration, neuronal cell damage, was reduced after the neprilysin gene transfer.
"If we find a way to shift the balance between amyloid production, clearance, and degradation, I believe we can find a way to interfere with the processes involved in Alzheimer's disease," says Gage. "Further study will help define the role of neprilysin in regulating amyloid and possibly treating or preventing AD."
Astrocytes, a type of cell which supports, nourishes, and protects neurons in the brain, are found around and are in contact with AD plaques. Husemann and colleages theorized that astrocytes near the AD plaques may not only immobilize or bind to abeta peptides in the brain, but might also degrade the abeta, which they found to be the case with adult mouse astrocytes.
The team then set out to see if adult astrocytes could also "process" abeta deposits from brain tissue. They incubated adult astrocytes on brain sections of transgenic mice making human APP. After 24 hours incubation with astrocytes, the area of the hippocampus occupied by abeta was reduced by 40 percent, Husemann and colleagues found. "The findings raise the intriguing possibility that defects in astrocyte cell clearance of abeta may contribute to the formation of AD plaques," notes Husemann. "Harnessing the protective function of these cells may be a strategy for AD prevention and treatment."
The NIA leads the Federal effort to support and conduct basic, clinical, and social and behavioral studies on aging and on AD. It supports the Alzheimer's Disease Education and Referral (ADEAR) Center, which provides information on AD research.
ADEAR's has several publications on the causes and course of AD, including the new publication Alzheimer's Disease: Unraveling the Mystery and the detailed Progress Report 2000 , which describes the broad Federal research program on AD.
The public and health professionals may also call ADEAR toll free, 1-800-438-4380. Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information Web site.