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November 7, 2003
Herpes research uncovers possible clue to Alzheimer's disease
WOODS HOLE, MA and PROVIDENCE, RI Researchers at the Marine Biological Laboratory (MBL) and Brown University have found a physical connection between the herpes simplex virus and amyloid precursor protein, a protein that breaks down to form a major component of the amyloid plaques that are consistently present in the brains of persons with Alzheimers disease.
Amyloid precursor protein - or APP - breaks down to form beta-amyloid. There is strong evidence, according to the researchers, that beta-amyloid is the underlying cause of Alzheimers.
While the scientists caution that no conclusions about Alzheimers can be drawn from their findings, Dr. Elaine Bearer, senior research scientist and associate professor in Browns Department of Pathology and Laboratory Medicine, believes the work does in fact link the common herpes virus of cold sores with the neurodegenerative disorder. Bearer is also a summer investigator at the MBL.
Past studies have implicated the herpes virus in the onset of Alzheimers disease, but agreement within the scientific community on the value of that research is far from universal. Bearer expects that the discovery of a physical interaction between APP and the herpes virus will trigger further investigations into the role the virus may play in the disease, and even into possible uses of the virus in therapy.
The scientists stress that none of what they found should cause alarm among those who have at one time had a cold sore. According to Bearer, nearly 85 percent of us harbor the herpes simplex virus and most of us never develop Alzheimers.
The researchers discovered the interaction between the herpes simplex virus (HSV) and APP while conducting experiments in the giant axon of squid at the MBL. Prasanna Satpute-Krishnan and Joseph A. DeGiorgis, both doctoral candidates in Browns graduate program at the time of the research, were seeking to learn how viruses are carried around the body - within cells and from one cell to another. Specifically, they were examining how the herpes simplex virus travels back to the lip area to form a recurring blister after remaining latent for some time in the trigeminal ganglion, a collection of nerve cells next to the brain.
What they found was that the herpes virus was interacting with APP, a putative motor receptor that recruits a microtubular motor, kinesin, for transport through neurons. This was the first time scientists had observed any physical interaction between the herpes virus and APP.
Without the APP, the virus moves backward up an axon (a long extension of a neuron) from the area of the lip towards the trigeminal ganglion. But the Brown researchers discovered that once it interacts with the APP, the virus travels in the opposite direction - what scientists describe as anterograde transport - back down to the lip. The researchers also found that once coupled with the APP, the virus moves remarkably fast.
"Its as if the virus hijacks a car - which in this case would be the kinesin - and the APP is the driver," explains Bearer. "The virus takes the APP where it wants to be, not where the APP wants to be."
The build-up of beta-amyloid (formed in the breakdown of APP) is found consistently in the brains of Alzheimers patients, and many scientists are now convinced it is involved in the disease, according to Satpute-Krishnan. Questions persist, however, as to what that involvement is, and why, when APP is found in all of us, it causes problems only in a few.
Perhaps, Bearer speculates, when the APP is co-opted by the herpes virus, the APP breaks down at a location where it would not normally appear - and at a very different rate. "When APP piles up around neurons, the neurons die," she explains. "But we dont yet know if this is a secondary or a primary cause of Alzheimers."
"At this point, of course, we dont yet know whether herpes plays a causal role in Alzheimers disease," DeGiorgis notes. "But our research does provide some interesting new insight into both diseases."
A paper outlining the findings of the MBL/Brown researchers - titled "Fast Anterograde Transport of Herpes Simplex Virus: Role of Amyloid Precursor Protein" - will appear in the December issue of Aging Cell, published by Blackwell Publishing in England and at the publishers "OnlineEarly" site.
Satpute-Krishnan, the first author of the paper, is a graduate student in Browns Molecular Biology, Cell Biology and Biochemistry Graduate Program. Bearer, who holds both an M.D. and a Ph.D., is an experimental pathologist. DeGiorgis, who earned his Ph.D. in Bearers lab last year, is now with the National Institutes of Health.
Experiments in this study were conducted in the giant axon of squid, a model widely used in research because with a diameter of nearly a millimeter it is 1,000 times thicker than a human axon. Researchers are able to inject substances into the giant axon and then observe the behavior of those substances through high-powered microscopes.
"It is pretty extraordinary that breakthroughs in Alzheimers disease and in the pathogenesis of herpes virus should be made using the squid of the North Atlantic sea," notes Bearer.
Last summer Brown University and the Marine Biological Laboratory formalized their alliance for teaching and research. The affiliation between the two institutions established the Brown-MBL Graduate Program in Biological and Environmental Sciences. In addition, it will promote faculty exchanges and research collaborations, such as the one conducted by Satpute-Krishnan, DeGiorgis and Bearer.
Bearer credits "the intimate cross-disciplinary culture at Brown" for inspiring and nurturing research such as hers. "Brown gerontologists interact on a daily basis with basic scientists who travel to the affiliated Marine Biological Lab to use exotic species as elegant model systems," she says, adding that Browns Center for Gerontology is considered one of the best in New England. The Dean of Medicine at Brown, Richard Besdine, is himself a gerontologist.
The affiliation between MBL and Brown takes advantage of the geographic proximity of the two institutions, uniting their faculty expertise in biology and medicine, particularly for molecular biology, genomics, ecosystems studies, environmental science, global infectious diseases, neuroscience and public health. Student recruitment for the Brown-MBL Graduate Program got under way this fall, with the first students expected to begin their studies next year.
The Marine Biological Laboratory is an internationally known, independent, nonprofit institution dedicated to improving the human condition through creative research and education in the biological, biomedical and environmental sciences. Founded in 1888, the MBL is the oldest private marine laboratory in the Western Hemisphere.