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Subject: VARIANT PRION PROTEIN CAUSES INFECTION BUT NO SYMPTOM


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VARIANT PRION PROTEIN CAUSES INFECTION BUT NO SYMPTOMS
Finding Could Have Implications for Alzheimer's Disease

Abnormal prion proteins are little understood disease agents involved in
causing horrific brain-wasting diseases such as Creutzfeldt-Jacob
disease in people, mad cow disease in cattle and chronic wasting disease
in deer and elk. Now, new research suggests that a variant form of
abnormal prion protein -- one lacking an "anchor" into the cell membrane
-- may be unable to signal cells to start the lethal disease process,
according to scientists at the Rocky Mountain Laboratories (RML), part
of the National Institute of Allergy and Infectious Diseases (NIAID) of
the National Institutes of Health.

"This work provides novel insights into how prion and other
neurodegenerative diseases develop and it provides tantalizing clues as
to how we might delay or even prevent such diseases by preventing
certain cellular interactions," notes NIAID Director Anthony S. Fauci,
M.D.

A paper describing the research was released online today by the journal
"Science". RML virologist Bruce Chesebro, M.D., directed the project.
Other key co-authors from the Hamilton, MT, RML laboratory include
Richard Race, D.V.M., and Gerald Baron, Ph.D. Their collaborators
included Michael Oldstone, M.D., and Matthew Trifilo, Ph.D., of The
Scripps Research Institute in La Jolla, CA, and Eliezer Masliah, M.D.,
of the University of California, San Diego (UCSD).

Drawing on experimental concepts first developed at RML a decade ago,
the research team exposed two groups of 6-week-old mice to different
strains of the agent that causes scrapie, a brain-wasting disease of
sheep. Within 150 days of being inoculated with the natural form of
scrapie prion protein, all 70 mice in the control group showed visible
signs of infection: twitching, emaciation and poor coordination. In
contrast, the scientists observed 128 transgenic mice -- those
engineered to produce prion protein without a glycophosphoinositol (GPI)
cell membrane anchor -- for 500 to 600 days and saw no signs of scrapie
disease. Subsequent electron microscopic examinations at UCSD, however,
confirmed that they produced amyloid fibrils, an abnormal form of prion
protein, and that they even had brain lesions. More remarkably,
according to Dr. Chesebro, the diseased brain tissue resembled that
found in Alzheimer's disease rather than in scrapie.

Chesebro mentions two theories as to why the transgenic mice did not
show symptoms of illness despite being infected:

The host cell might require the GPI anchor to receive the "toxic signal"
from the abnormal prion protein The plaques might be less toxic than the
non-plaque form of prion protein clumps In either case, more time might
be required to produce disease due to the reduced toxicity, Dr. Chesebro
says.

"There was so much about this research that surprised us and gave us
ideas to pursue," says Dr. Chesebro. "First, the mice didn't get sick.
That's very significant. Second, the dense accumulations of scrapie
plaque in the brain resembled the plaque seen in Alzheimer's, but it
wasn't toxic," which might support more recent concepts about plaque in
Alzheimer's patients. "Previously, most researchers thought plaques were
the toxic component of Alzheimer's that kills neurons, and many
treatments focus on removing the plaques. But what if the plaques are
inert, as they were in this research? What if only small clumps are
toxic?"

If this hypothesis proves correct, Dr. Chesebro says, the ongoing
research could eventually alter scientists' views on preventing prion
diseases, shifting emphasis away from stopping the production of prion
protein clumps and toward preventing interactions with prion protein
anchored to cells, or learning to direct abnormal prion protein
accumulations to specific parts of the brain where they will not produce
symptoms.

"Abnormal prion protein by itself may not be rapidly lethal -- in these
mice it wasn't," Dr. Chesebro says.

To view an image that shows how abnormal prion proteins also appear as
plaques in the brains of scrapie-infected mice expressing anchorless
prion proteins, please visit
http://www.nih.gov/news/pr/jun2005/niaid-02.htm.

NIAID is a component of the National Institutes of Health, an agency of
the U.S. Department of Health and Human Services. NIAID supports basic
and applied research to prevent, diagnose and treat infectious diseases
such as HIV/AIDS and other sexually transmitted infections, influenza,
tuberculosis, malaria and illness from potential agents of bioterrorism.
NIAID also supports research on transplantation and immune-related
illnesses, including autoimmune disorders, asthma and allergies.

News releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at http://www.niaid.nih.gov.

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Reference: B Chesebro et al. Anchorless prion protein results in
infectious amyloid disease without clinical scrapie. "Science". DOI:
10.1126/science.1110837.
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