Category: Mad Cow Disease

NewsPsychology (Jan. 24, 2007) — A single protein plays a major role in deadly prion diseases by smashing up clusters of these infectious proteins, creating the “seeds” that allow fatal brain illnesses to quickly spread, new Brown University research shows.

The findings are exciting, researchers say, because they might reveal a way to control the spread of prions through drug intervention. If a drug could be made that inhibits this fragmentation process, it could substantially slow the spread of prions, which cause mad cow disease and scrapie in animals and, in rare cases, Creutzfeldt-Jacob disease and kuru in humans.

Because similar protein replication occurs in Alzheimer’s and Parkinson’s diseases, such a drug could also slow progression of these diseases as well.

“The protein fragmentation we studied has a big impact on how fast prion diseases spread and may also play a role in the accumulation of toxic proteins in neurodegenerative diseases like Parkinson’s,” said Tricia Serio, an assistant professor in Brown’s Department of Molecular Biology, Cell Biology and Biochemistry and lead researcher on the project.

The findings from Serio and her team, which appear online in PLoS Biology, build on their groundbreaking work published in Nature in 2005. That research showed that prions – strange, self-replicating proteins that cause fatal brain diseases – convert healthy protein into abnormal protein through an ultrafast process.

This good-gone-bad conversion is one way that prions multiply and spread disease. But scientists believe that there is another crucial step in this propagation process – fragmentation of existing prion complexes. Once converted, the thinking goes, clusters of “bad” or infectious protein are smashed into smaller bits, a process that creates “seeds” so that prions multiply more quickly in the body. Hsp104, a molecule known to be required for prion replication, could function as this protein “crusher,” Serio thought.

To test these ideas, Serio and members of her lab studied Sup35, a yeast protein similar to the human prion protein PrP. They put Sup35 together with Hsp104, then activated and deactivated Hsp104. They found that the protein does, indeed, chop up Sup35 complexes – the first direct evidence that this process occurs in a living cell and that Hsp104 is the culprit.

“To understand how fragmentation speeds the spread of prions, think of a dandelion,” Serio said. “A dandelion head is a cluster of flowers that each carries a seed. When the flower dries up and the wind blows, the seeds disperse. Prion protein works the same way. Hsp104 acts like the wind, blowing apart the flower and spreading the seeds.”

Serio said that prions still multiply without fragmentation. However, she said, they do so at a much slower rate. So a drug that blocked the activity of Hsp104 could seriously slow progression of prion-related diseases.

Former graduate student Prasanna Satpute-Krishnan and research associate Sara Langseth, also in Brown’s Department of Molecular Biology, Cell Biology and Biochemistry, conducted the work with Serio.

The National Cancer Institute, the National Institute of General Medical Sciences, and the Pew Scholars Program in the Biomedical Sciences funded the research.

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The above story is reprinted (with editorial adaptations by newsPsychology staff) from materials provided by Brown University.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of NewsPsychology or its staff.

The U.S. Department of Agriculture's Agricultural Research Service (ARS) have announced initial results of a research project involving prion-free cattle. ARS scientists evaluated cattle that have been genetically modified so they do not produce prions, and determined that there were no observable adverse effects on the animals' health.

"These cattle can help in the exploration and improved understanding of how prions function and cause disease, especially with relation to bovine spongiform encephalopathy, or BSE," said Edward B. Knipling, administrator of ARS. "In particular, cattle lacking the gene that produces prions can help scientists test the resistance to prion propagation, not only in the laboratory, but in live animals as well."

Prions are proteins that are naturally produced in animals. An abnormal form of prion is believed to cause devastating illnesses called transmissible spongiform encephalopathies (TSEs), the best known of which is BSE.

ARS studied eight Holstein males that were developed by Hematech Inc., a pharmaceutical research company based in Sioux Falls, S.D. The evaluation of the prion-free cattle was led by veterinary medical officer Juergen Richt of ARS' National Animal Disease Center (NADC) in Ames, Iowa. The evaluation revealed no apparent developmental abnormalities in the prion-free cattle.

Richt said, "The cattle were monitored for growth and general health status from birth up to 19 months of age. Mean birth and daily gain were both within the normal range for Holsteins. General physical examinations, done at monthly intervals by licensed veterinarians, revealed no unusual health problems."

ARS, with assistance from researchers at Hematech and the University of Texas, evaluated the cattle using careful observation, post-mortem examination of two of the animals, and a technology that amplifies abnormal proteins to make them easier to detect. Further testing will take at least three years to complete.

The evaluation was reported today in the online version of the scientific journal Nature Biotechnology. ARS is USDA's chief intramural scientific research agency.

A new method of treatment can appreciably slow down the progress of the fatal brain disease scrapie in mice. This has been established by researchers from the Universities of Munich and Bonn together with their colleagues at the Max Planck Institute in Martinsried. To do this they used an effect discovered by the US researchers Craig Mello and Andrew Fire, for which they were awarded this year's Nobel Prize for Medicine. Scrapie is a variant of the cattle disease BSE (bovine spongiform encephalopathy, also known as 'mad cow disease') and the human equivalent Creutzfeld-Jakob disease. However, it will take years for the method to be introduced to medicine, the researchers warn. Their findings are published in the next issue of the Journal of Clinical Investigation (Vol. 116, No. 12, December 2006).

Scrapie, Creutzfeld-Jakob and BSE are among the most unusual diseases known to medical research. Unusual because the pathogens are apparently neither viruses nor bacteria, being simply protein molecules known as protein prions. What is even more peculiar: exactly the same prion proteins occur in healthy animals. The only difference is that they have a different shape. When there is contact with their 'diseased twins' they change their shape, also becoming 'diseased.' The result is an irresistible chain reaction. The malformed prion proteins can be deposited in the brain, thereby destroying brain tissue. Prion diseases are always fatal, often, however, not until months after the outbreak of the disease. As yet there is no cure.

In mice suffering from scrapie the pathogenic prion protein is known as PrP-Scr, whereas the normal variant is PrP-C. PrP-C seems to have a protective effect in diseases like a stroke. Interestingly, mice which cannot produce any PrP-C appear to be completely healthy. This has become the starting point for a new therapeutic approach which for some years now has been current in research circles: can we not simply switch off the production of 'healthy' PrP-C in infected animals, thereby depriving the 'diseased' PrP-Scr of its ability to spread" In this way the chain reaction would be interrupted.

New therapeutic approach

Scientists from Munich's Ludwig Maximilian University and the University of Bonn, in conjunction with colleagues from the Max Planck Institute in Martinsried, have been testing whether this approach works. In doing so they cut back the production of PrP-C in mice by means of an ingenious procedure. The researchers used a special RNA molecule for this purpose. RNA is related to the genetic molecule DNA. There are types of RNA known as siRNAs which can attach themselves to specific genes, thereby preventing these from being 'read'. The production of the appropriate protein is thus shut down. This effect is known as RNA interference; its discovery was rewarded with this year's Nobel Prize for Medicine. "We modified the brain cells of mice in such a way that they were able to produce siRNAs in place of the 'healthy' PrP-C protein," explains Professor Alexander Pfeifer, director of the Institute of Pharmacology of the University of Bonn. "In cell cultures the production of PrP-C was thereby cut back by up to 97 per cent."

The researchers then tested what effect these siRNAs had on mice which had scrapie. 'If brain cells are to produce siRNAs, you have to smuggle in the corresponding gene,' says Professor Kretschmar, director of the Prion Centre of Munich's Ludwig Maximilian University. 'But presumably we'll never manage to equip all the cells in the brain with this gene.' This is why the researchers also wanted to find out how many cells they have to 'revamp' genetically to treat scrapie or similar diseases successfully. For this purpose they bred mice that only had some brain cells which could produce siRNAs. 'Whereas the untreated mice died on average after 165 days, the mice which had been treated lived appreciably longer,' is how Professor Kretschmar summarises the results.

BSE-resistant cattle

It varied how much longer they lived: if only a few cells could produce siRNAs, the mice died at almost the same time as the control mice, i.e. on average after 170 days. However, if the majority of the brain cells were protected by siRNA, the mice survived the prion disease for up to 230 days, in other words about a third longer.

'Basically siRNAs seem to be a promising therapeutic option for scrapie, CJD or BSE,' Professor Pfeifer emphasises. 'However, it will take years before the method can be used on human beings.' The method is also relevant for animal breeding: in principle it can be used to breed cattle which cannot produce any PrP-C. They would then be resistant to BSE.

 Researchers at the Animal Health Research Centre (CReSA) are developing immunotherapeutical strategies against diseases produced by prion, such as Bovine Spongiform Encephalitis. The most recent results, published in the Journal of Virology, show that important advances have been made in tests using DNA vaccines on animal models, enabling a significant delay in the arrival of symptoms. In the long term, this research could lead to the production of treatment for humans.

The infectious agent responsible for transmissible spongiform encephalopathies, also known as prion diseases, (which include mad cow disease), is a protein known as the infectious prion (PrPi), which has no nucleic acid and which produces contagious neurodegenerative diseases in different species of animals. The PrPi changes shape to that of an existing natural protein in the organism, the cellular prion (PrPc), but does not change its amino acid sequence. In certain circumstances, when the PrPi comes into contact with the original proteins, the proteins take on the shape of the in the infectious protein. Once this accumulates in the central nervous system, it destroys neural mass and makes the brain of affected animals take on a sponge form, which is where the term "spongiform diseases" comes from.

The researchers' work focuses on producing a vaccine that will provide an immune response that is as complete as possible, including both a humoral response (production of antibodies) and a cellular response (eliminating "infected" cells and activating the "memory", enabling the animal cells to continue responding to the infectious agent).

The main obstacle to achieving this objective is that the prions do not produce an immune response since the metabolism of the affected animal identifies it as one of its own antigens. The challenge, therefore, is to overcome the tolerance barrier, that is, that the animal's body produces an immune response to one of its antigens.

The researchers have achieved this objective using a DNA vaccine based on a plasmid (an extrachromosomal DNA molecule) that expresses the prion gene with a small sequence that acts as a transport signal to cellular compartments called lysosomes. Once the vaccination is administered, the prion quickly degrades in the lysosome, allowing a marked improvement in the presentation of the cells of the immune system and inducing a powerful antibody and cellular response.

The results of the research have shown that in vaccinated mice, and only in those vaccinated, there is a significant delay in the appearance of symptoms after the intracerebral infection produced by the infectious prion.

The group is continuing its research to further investigate new administration routes for the vaccine and to eliminate the side effects observed in vaccinated animals.

This work may also enable advances to be made in the development of reactive agents for the diagnosis of diseases produced by the prion that until now could only be achieved post mortem.

— The urgent search for a medication to treat prion diseases has led scientists in Germany to synthesize a new group of compounds, including one that is 15 times more potent than an approved drug now being tested in clinical trials.

Their report is scheduled for the Nov. 2 issue of the biweekly ACS Journal of Medicinal Chemistry.

Prions are infectious proteins that cause brain disorders like Mad Cow Disease and Creutzfeldt-Jakob Disease (CJD) in humans. Peter Gmeiner and colleagues note that the recent emergence of a new form of CDJ, linked to consumption of infected beef mainly in Great Britain, intensified the search for anti-prion compounds.

Most potential drugs have proved ineffective, often because they could not enter brain tissue where prions reside. One promising drug, however, is in clinical trials. That drug is quinacrine, already approved for several other medical conditions.

Gmeiner's group describes the chemical synthesis and early laboratory testing of a family of anti-prion compounds that cross into brain tissue and combat prions. One of those compounds has what the report describes as "unprecedented" anti-prion activity, with 15 times greater potency than quinacrine.

 A study published in the online edition of the Journal of the Royal Society Interface has been exploring the likelihood that variant Creutzfeldt-Jakob disease might be spread via the reuse of surgical instruments, and calls for more data in order to allay fears over the possible transmission of vCJD.

[Editor's Note: Variant Creutzfeldt-Jakob disease (vCJD) has been linked to bovine spongiform encephalopathy (BSE), commonly known as 'mad cow' disease — a progressive neurological disorder of cattle that results from infection by an unconventional transmissible agent. Strong evidence indicates that BSE has been transmitted to humans primarily in the United Kingdom, causing a variant form of Creutzfeldt-Jakob disease (vCJD), according to the U.S. Centers for Disease Control and Prevention. (See: http://www.cdc.gov/ncidod/dvrd/vcjd/qa.htm.)]

The number of vCJD cases continues to decline, and it is believed that most cases to date are the result of consumption of BSE-infected beef. There were 161 recorded cases by the end of 2005, and the annual incidence has been steadily decreasing since 2000, with estimates for the total scale of the epidemic through this route now lie in the low hundreds.

However, concern has been raised that transmission could, in theory, occur directly from one person to another via routes such as blood transfusions and surgical operations, despite instruments being decontaminated routinely before being used. Scientists based at both the London School of Hygiene & Tropical Medicine and the National Creutzfeldt-Jakob Disease Surveillance Unit at Western General Hospital in Edinburgh decided to explore this possibility.

The results, published online today by the Journal of the Royal Society Interface, show that key factors determining the scale of any epidemic are the number of times a single instrument is re-used, combined with how infectious contaminated instruments are and how effective the cleaning is.

The authors begin by presenting data on the surgical procedures undertaken on vCJD patients prior to the onset of clinical symptoms which support the hypothesis that cases via this route are possible. They then apply a mathematical framework to assess the potential for self-sustaining epidemics via surgical procedures.

They conclude that further research is needed into how surgical instruments are used so as to reduce uncertainty and assess the potential risk of this transmission route.

They comment: 'Given the frequency of high- and medium-risk surgical procedures undertaken in the UK, a range of plausible scenarios suggest that surgical procedures could provide a potential route for a self-sustaining epidemic of vCJD. A first step to reducing the current uncertainty in the potential for self-sustaining transmission via surgery would be to survey the frequency with which different instruments are used, particularly those used on high-infectivity procedures. Also, tracking of surgical instruments should be improved, so that, at the very least, instruments are not re-used once the infection status of a patient is known'.

Reference: Factors determining the potential for onward transmission of vCJD via surgical instruments (doi:10.1098/rsif.2006.0142) by Tini Garske1, Hester JT Ward2, Paul Clarke1, Robert G Will2, Azra Ghani1.

1Department of Epidemiology and Population Heal th, London School of Hygiene & Tropical Medicine

2National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, Edinburgh

According to the World Health Organization, variant Creutzfeldt-Jakob disease (vCJD) is a rare and fatal human neurodegenerative condition. As with Creutzfeldt-Jakob disease, vCJD is classified as a Transmissible Spongiform Encephalopathy (TSE) because of characteristic spongy degeneration of the brain and its ability to be transmitted. vCJD is a new disease that was first described in March 1996.

 A team of researchers at The Scripps Research Institute, the University of California, San Diego (UCSD), and Rocky Mountain Laboratories of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), has shown for the first time that laboratory mice infected with the agent of scrapie — a brain-wasting disease of sheep-demonstrate high levels of the scrapie agent in their heart 300 days after being infected in the brain.

These findings raise the possibility that heart infection could be a new aspect of prion diseases, including those that affect humans and livestock, and that these diseases could travel through the blood.

The paper is being published on Friday, July 7 in an advanced, online edition of the journal Science.

Prion diseases-also known as transmissible spongiform encephalopathies because of the sponge-like holes created in the brain-include scrapie in sheep, mad cow disease in cattle, chronic wasting disease in deer and elk, and new variant Creutzfeldt-Jacob disease in humans. These diseases are unusual because unlike other infectious diseases, prion diseases appear to be transmitted by a protein, specifically a misfolded form of a normal cellular protein, the prion.

"Until now, prion disease has been thought of as a chronic neurological condition," says Scripps Research Professor Michael B. Oldstone, M.D., who led the research. "Our study has shown, however, that it can have other manifestations, therefore expanding the types of conditions it could cause."

In the newly reported study, investigators at Scripps Research found infectious misfolded prion protein in heart muscle. Although several types of protein are known to form heart amyloid, this is the first time prion protein amyloid in heart tissue has been identified. Only misfolded prion proteins are infectious.

After making this surprising finding, Scripps Research investigators secured the help of Kirk Knowlton, M.D., chief of the division of cardiology at the University of California, San Diego, who investigated the effect of prion protein amyloid on mouse heart function, discovering that it decreased the heart's ability to pump blood.

Significantly, unusually high levels of scrapie infectivity were also identified in the blood of the same mice used in the heart study. "This is the first system in which prion disease agents were found reproducibly and reliably at high titers in the blood," notes Oldstone.

In the future, this finding could help scientists answer basic questions such as how prions travel in the bloodstream, as well as develop such important applications as a blood-based diagnostic test to identify brain-wasting diseases and possibly a way to filter or chemically treat blood to remove any infectious prion disease agents. Currently, in the United States individuals who lived in the United Kingdom for three months or more during the outbreak of mad cow disease from 1980 to 1996 are asked not to donate blood. In the United Kingdom, only individuals born after the outbreak may donate.

The new research will also provide scientists with an animal model in which to study heart amyloidosis, a family of heart diseases that affect humans. Amyloidoses involve waxy protein deposits that stiffen the heart, limit its pumping ability, and typically lead to fatal heart stoppage.

"Undoubtedly, this work will enable scientists to pursue new theories about the effects of these deadly brain wasting diseases," says NIH Director Elias A. Zerhouni, M.D. "The implications of this research could be vital to our efforts to slow or stop these diseases."

The new research follows last year's finding from the Oldstone group in collaboration with Bruce Chesebro, M.D., at the NIH's Rocky Mountain Laboratories, which suggested a specific part of the prion protein is essential for the pathogenesis of prion diseases (Science (308 (5727):1435-39 (2005)). In this study, the investigators engineered scrapie-infected mice without an "anchor"-specifically the glycophosphoinositol anchor, a stretch of amino acids at the COOH end of the protein-between the membrane of cells and the prion protein. By taking off this anchor, the researchers showed that the prion protein still folded but was no longer able to attach in normal amounts onto the surface of cells. In contrast to scrapie-infected wild mice, which typically die after about 150 days, the engineered mice regularly lived for more than 600 days with minimal symptoms, ultimately dying of old age.

In prion diseases, the normal form of the prion protein is converted into an abnormal, misfolded form. Disease occurs because these abnormal proteins have the ability to convert normal prion proteins into the abnormal form. Like bad apples spoiling the lot, the infectious prions will multiply, and their insolubility will lead to their aggregation and the formation of plaques, which can interfere with normal function in the brain.

Of the prion diseases, most in the news has been bovine spongiform encephalopathy, or mad cow disease, which has caused widespread public concern over the last two decades after it has appeared primarily in cattle in England but also in other countries in Europe, Canada, and the United States. Perhaps the number one reason why a disease that infects cows is of such concern to world governments is that scientists believe that the disease can be transmitted across species through the consumption of tainted meat from a diseased animal's central nervous system. The first major outbreak of mad cow disease in Britain is believed to have originated with the now outlawed practice of feeding cattle meat and bone meal derived from other slaughtered animals. Chronic wasting disease in U.S. deer and elk is also of concern, as the abnormal protein has been found in both wild and farmed animals.

Scientists now know that humans who eat meat from BSE-infected cattle may be susceptible to the prion disease new variant Creutzfeldt-Jakob. There are now more than 140 such cases. This incurable disease is named after a similar condition called Creutzfeldt-Jakob disease, after the German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob, who first diagnosed it. Creutzfeldt-Jakob disease most commonly strikes older people, and it causes neurologic abnormalities, dementia, memory loss, hallucinations, seizures, and eventually death. New variant Creutzfeldt-Jakob is similar clinically, but can strike much younger people. According to the U.S. Centers for Disease Control and Prevention, the median age of death for Americans with Creutzfeldt-Jakob disease is 68, whereas the median age of death of people with new variant Creutzfeldt-Jakob in Great Britain, where most cases have occurred, is 28.

Authors of the newly released study, entitled "Prion-induced amyloid heart disease with high blood infectivity in transgenic mice," (Science, 313:94-97 (2006)) are: Matthew J. Trifilo, Toshitaka Yajima, Yusu Gu, Nancy Dalton, Kirk L. Peterson, Richard E. Race, Kimberly Meade-White, John E. Portis, Eliezer Masliah, Kirk Knowlton, Bruce Chesebro, and Michael B.A. Oldstone.

The research was supported by a program project grant for the study of prion disease from the NIH's National Institute on Aging.

 In the July 7, 2006, issue of the journal Science, researchers at the University of Texas Medical Branch at Galveston (UTMB) describe experiments that may soon lead to a test that will enable medical science to estimate how many people are infected with the human form of mad cow disease, which can take as long as 40 years before manifesting itself.

Such a blood test could also help prevent accidental transmission of the malformed proteins that cause variant Creutzfeldt-Jakob disease (vCJD) via blood transfusions and organ transplants, the scientists suggest.

Done in hamsters, the experiments are the first ever to biochemically detect the malformed proteins during the "silent phase" of the disease–just weeks after the animals were infected and months before they showed clinical symptoms.

The scientists say that they detected prions–the infectious proteins responsible for such brain-destroying disorders as bovine spongiform encephalopathy (BSE) in cattle and vCJD in humans–in the blood of the hamsters in as few as 20 days after the animals had been infected. That discovery occurred about three months before the hamsters began showing clinical symptoms of the disease, the Science paper reports.

To detect the very small quantities of prions found in blood samples, UTMB professor Claudio Soto, assistant professor Joaquin Castilla and research assistant Paula Saá used a technique known as protein misfolding cyclic amplification (PMCA), invented by Soto's group, which greatly accelerates the process by which prions convert normal proteins to misshapen infectious forms.

"With this method, for the first time we have detected prions in what we call the silent phase of infection, which in humans can last up to 40 years," said Soto, senior author of the Science paper.

"The concern is that if many people are incubating the disease silently, then secondary transmission from human to human by blood transfusion or surgical procedures could become a big problem," he continued. "This result is an important step toward a practical biochemical test that will determine how common variant CJD is, and keep contaminated blood and organs from spreading it further."

Creating such a test is a high priority for Soto, who is also director of UTMB's George and Cynthia Mitchell Center for Alzheimer's Disease. "We're now working with natural samples, both from humans and cattle but mostly from humans," he said. With an eye toward making a human test commercially available, Soto and UTMB recently formed a startup company, dubbed "Amprion."

"All our effort so far has been to prove the scientific concepts, so we're building this company to go into issues of development, scalability and practicality," Soto said. "We are hopeful that development of this technology into a useful blood test will be a pretty straightforward process."

— Brittleness is often seen as a sign of fragility. But in the case of infectious proteins called prions, brittleness makes for a tougher, more menacing pathogen. Howard Hughes Medical Institute researchers have discovered that brittle prion particles break more readily into new “seeds,” which spread infection much more quickly.

The discovery boosts basic understanding of prion infections, and could provide scientists with new ideas for designing drugs that discourage or prevent prion seeding, said the study's senior author Jonathan Weissman, a Howard Hughes Medical Institute investigator at the University of California, San Francisco (UCSF).

Weissman and colleagues from UCSF reported their findings on June 28, 2006, in an advance online publication in Nature.

The scientists studied yeast prions, which are similar to mammalian prions in that they act as infectious proteins. In recent years, mammalian prions have gained increasing notoriety for their roles in such fatal brain-destroying human diseases as Creutzfeldt-Jakob disease and kuru, and in the animal diseases, bovine spongiform encephalopathy (“mad cow” disease) and scrapie.

Yeast and mammalian prions are proteins that transmit their unique characteristics via interactions in which an abnormally shaped prion protein influences a normal protein to assume an abnormal shape. In mammalian prion infections, these abnormal shapes trigger protein clumping that can kill brain cells. In yeast cells, the insoluble prion protein is not deadly; it merely alters a cell's metabolism. Prions propagate themselves by division of the insoluble clumps to create “seeds” that can continue to grow by causing aggregation of more proteins.

In earlier studies, Weissman and his colleagues had discovered that the same prion can exist in different strains and have different infectious properties. These strains arise from different misfoldings of the prion protein that result in different conformations. A similar strain phenomenon has been described for mammalian prions. More generally, even in noninfectious diseases involving protein misfolding, like Alzheimer's and Parkinson's diseases, the same protein can misfold into more than one shape with some forms being toxic and others benign. However, Weissman said, it was not understood how different conformations cause different physiological effects.

As part of the studies published in Nature, the researchers created a mathematical model that enabled them to describe the growth and replication of prions according to the physical properties of the prion protein. To validate that model in yeast, they then created in a test tube, infectious forms of the prion protein in three different conformations and introduced them into yeast cells. They then correlated the strength of infectivity of each prion with its physical properties and compared their results to those predicted by their mathematical model.

According to Weissman, the researchers found that the slowest-growing conformation seemed to have the strongest effect in producing protein aggregates inside cells. “But we knew from our model that growth was only half of the equation,” said Weissman. “The other key feature was how easy it was to break up the prion and create new seeds, and this propensity to seed could be an important determinant of the prion's physiological impact. And that is what we found experimentally — that the slower growth of that conformation was more than compensated for by an increased brittleness that promotes fragmentation.”

According to Weissman, the importance of a prion's brittleness, or “frangibility,” to its physiological effects has both basic research and clinical implications. “Investigators trying to develop synthetic prions as a research model for mammalian prions have had a very hard time getting a high degree of activity,” he said. “Part of the reason may be that they were trying to create forms that were very stable. But that might have been exactly the wrong thing to do, because prions that are too stable may be the ones that are not very infectious because the aggregates are hard to break up.

“And from a therapeutic point of view, our findings suggest that effective treatment strategies for prion diseases might aim at stabilizing prion aggregates. By preventing the aggregates from being broken up to smaller seeds, their propagation can be reduced. In contrast, most such strategies now aim at preventing the aggregates from forming in the first place,” he said.

In future studies, Weissman and his colleagues plan to expand their analytical model to describe in more detail how prions' physical properties lead to different physiological effects. They also plan more detailed analyses to examine how the molecular structure of a prion protein gives rise to its physical properties.

An exciting new tracer allows visualization of abnormal protein deposits—called amyloid plaques—in human diseases like Alzheimer’s and Creutzfeldt-Jakob and in prion diseases in animals like scrapie (similar to mad cow disease), according to researchers at the University of Pennsylvania and CHRU Tours in France. Their results were presented June 3–7 during SNM’s 53rd Annual Meeting in San Diego.

“This amyloid tracer IMPY—which detects amyloid plaques in the human brain—provides an excellent starting point for parallel research in humans and animals,” said Denis Guilloteau, a biophysics professor and radiopharmacist in the nuclear medicine department of the Centre Hospitalier Universitaire Tours (CHRU) in France. “With IMPY, we were able to visualize abnormal protein in both neurodegenerative diseases—Alzheimer’s and scrapie—and this could provide new directions for future research,” he added. There are similarities between the loss of brain function in prion diseases and in Alzheimer’s disease, and an understanding of prion diseases will add to the understanding of what happens to the brain with Alzheimer’s disease, explained the co-author of “IMPY, a Beta-Amyloid Imaging Probe for Prion Detection.” In addition, the tracer may be used for research in the veterinary field, he noted.

Alzheimer’s disease is a progressive, irreversible brain disorder with no known cause or cure. Symptoms may include memory loss, confusion, impaired judgment, disorientation and loss of language skills. More than 4.5 million Americans are believed to have Alzheimer’s disease, and by 2050, the number could increase to 13.2 million.

Prions are abnormal, transmissible agents—with no DNA—that are able to induce abnormal folding of normal cellular prion proteins in the brain, leading to brain damage and the characteristic signs and symptoms of the disease. Prions cause a number of rare progressive neurodegenerative disorders that affect both humans and animals, and the diseases are usually rapidly progressive and always fatal. Creutzfeldt-Jakob disease is a rare, degenerative human brain disorder. Scrapie is a degenerative disease that affects the nervous systems of sheep and goats, and it is related to mad cow disease. Currently, a brain autopsy is necessary to obtain a definite diagnosis for Alzheimer’s and Creutzfeldt-Jakob. Guilloteau noted that investigating the prion animal diseases could form a model for future research in human disease. “It is important to study human neurodegenerative diseases and animal prion diseases in parallel,” he said.

Developing molecular agents such as IMPY may be useful for diagnosis and monitoring the progression of Alzheimer’s, noted Guilloteau. “The beta-amyloid tracer—developed by University of Pennsylvania researchers—is a very promising tool that may be used to discern an early diagnosis of Alzheimer’s with single photon emission computed tomography (SPECT), an imaging method available in many hospitals,” he added.

In the study, researchers used radioiodinated IMPY to bind to prion deposits in infected mice brain sections. Autoradiography, a procedure where an image is produced on photographic film by the radiation from a radioactive substance, showed a good visualization of these prion deposits, said Guilloteau. Major accumulations of radioactivity were seen in the cortex, colliculus, hippocampus, thalamus, cerebellum and pons. “Additional work needs to focus on the progression of disease in our animal model in vivo, and we must correlate the images with clinical symptoms,” he added.