Category: Mad Cow Disease

Scrapie is a neurodegenerative disease which can function as a model for other diseases caused by an accumulation of proteins resulting in tissue malformations (proteinpathies), such as Alzheimer's and Parkinson's disease. Many questions regarding these diseases still remain unanswered. A new doctoral study has uncovered a number of factors relating to the uptake of the prion protein (PrP^Sc) associated with the development of this disease and how this protein interacts with the immune cells in the intestines.

Scrapie in sheep belongs to a group of diseases called "Transmissible spongiform encephalopathies"(TSE) because they are transmitted between individual animals and produce sponge-like, degenerative changes in the brain. These diseases afflict not only sheep but also cattle (BSE), deer (CWD) and humans (CJD). They can to a certain extent also be transmitted between species, as was the case during the 1990s, when over 200 people were infected by food and contracted CJD.

TSE, otherwise known as prion diseases, are thought to be transmitted by means of a diseased variant of a protein, the prion protein, which is a normal component of body cells and is most prolific in the brain. Generally speaking, prion diseases may be infectious, hereditary or occur sporadically/spontaneously. Disease arises when the normal prion protein mutates to the diseased variant, which differs from the healthy prion proteins by its change in structure. The body's cells have difficulty in breaking down this prion protein due to its different structure, and it therefore accumulates.

SInce PrP^Sc is to be found in the lymphatic tissue of the intestinal system at an early stage of the disease, it is assumed that transmission occurs via the gastrointestinal tract. During her doctoral research, veterinary scientist Caroline Piercey Åkesson studied the uptake of the prion protein in the intestines, thereby throwing new light on processes occurring during the early phase of the disease's development. Contrary to earlier assumptions, she demonstrated by means of immunoelectron microscopy that the prion protein responsible for the disease is not transported directly from the intestines to lymphatic tissue associated with the intestines. On the contrary, she showed that the protein passed freely or in lymphatic cells outside the organised lymphatic tissue in the intestines.

Dendritic cells are presumed to function as "gatekeepers" which determine what the body can tolerate and which immune defence reactions it needs to instigate when confronted with foreign substances. One of the objectives of Åkesson's project was therefore to examine the interaction of dendritic cells with prion protein uptake. Firstly, it was necessary to characterise dendritic cells in healthy sheep intestines and secondly, to investigate which types of cells were associated with the uptake of the prion protein.

Her findings showed that it was not dendritic cells, but macrophages, which were mainly responsible for the uptake of the protein. Åkesson's study revealed that the prion protein makes use of the normal physiological uptake channel for macromolecules in the intestines and that this may have a significant effect on the body's immunological surveillance system. One possible consequence is that immuno-tolerance is stimulated, thus impeding a normal immuno reaction against the prion protein absorbed via the intestines.

Future studies which can reveal how immunological cells are transported and how the prion protein is processed in the body will be of great interest, not only in order to provide more knowledge about scrapie, but also about other neurodegenerative proteinpathies, both in humans and animals.

Cand.med.vet. Caroline Piercey Åkesson defended her doctoral thesis on 20^th December 2011 at The Norwegian School of Veterinary Science. The thesis is entitled: Studies on the uptake of prions and their early interaction with immune cells of the sheep gut.

Researchers from the Centers for Disease Control and Prevention (CDC) have examined the potential for human exposure to prion diseases, looking at hunting, venison consumption, and travel to areas in which prion diseases have been reported in animals. Three prion diseases in particular — bovine spongiform encephalopathy (BSE or "Mad Cow Disease"), variant Creutzfeldt-Jakob disease (vCJD), and chronic wasting disease (CWD) — were specified in the investigation.

The results of this investigation are published in the June issue of the Journal of the American Dietetic Association.

"While prion diseases are rare, they are generally fatal for anyone who becomes infected. More than anything else, the results of this study support the need for continued surveillance of prion diseases," commented lead investigator Joseph Y. Abrams, MPH, National Center for Emerging and Zoonotic Infectious Diseases, CDC, Atlanta."But it's also important that people know the facts about these diseases, especially since this study shows that a good number of people have participated in activities that may expose them to infection-causing agents."

Although rare, human prion diseases such as CJD may be related to BSE. Prion (proteinaceous infectious particles) diseases are a group of rare brain diseases that affect humans and animals. When a person gets a prion disease, brain function is impaired. This causes memory and personality changes, dementia, and problems with movement. All of these worsen over time. These diseases are invariably fatal. Since these diseases may take years to manifest, knowing the extent of human exposure to possible prion diseases could become important in the event of an outbreak.

CDC investigators evaluated the results of the 2006-2007 population survey conducted by the Foodborne Diseases Active Surveillance Network (FoodNet). This survey collects information on food consumption practices, health outcomes, and demographic characteristics of residents of the participating Emerging Infections Program sites. The survey was conducted in Connecticut, Georgia, Maryland, Minnesota, New Mexico, Oregon, and Tennessee, as well as five counties in the San Francisco Bay area, seven counties in the Greater Denver area, and 34 counties in western and northeastern New York.

Survey participants were asked about behaviors that could be associated with exposure to the agents causing BSE and CWD, including travel to the nine countries considered to be BSE-endemic (United Kingdom, Republic of Ireland, France, Portugal, Switzerland, Italy, the Netherlands, Germany, Spain) and the cumulative length of stay in each of those countries. Respondents were asked if they ever had hunted for deer or elk, and if that hunting had taken place in areas considered to be CWD-endemic (northeastern Colorado, southeastern Wyoming or southwestern Nebraska). They were also asked if they had ever consumed venison, the frequency of consumption, and whether the meat came from the wild.

The proportion of survey respondents who reported travel to at least one of the nine BSE endemic countries since 1980 was 29.5%. Travel to the United Kingdom was reported by 19.4% of respondents, higher than to any other BSE-endemic country. Among those who traveled, the median duration of travel to the United Kingdom (14 days) was longer than that of any other BSE-endemic country. Travelers to the UK were more likely to have spent at least 30 days in the country (24.9%) compared to travelers to any other BSE endemic country. The prevalence and extent of travel to the UK indicate that health concerns in the UK may also become issues for US residents.

The proportion of survey respondents reporting having hunted for deer or elk was 18.5% and 1.2% reported having hunted for deer or elk in CWD-endemic areas. Venison consumption was reported by 67.4% of FoodNet respondents, and 88.6% of those reporting venison consumption had obtained all of their meat from the wild. These findings reinforce the importance of CWD surveillance and control programs for wild deer and elk to reduce human exposure to the CWD agent. Hunters in CWD-endemic areas are advised to take simple precautions such as: avoiding consuming meat from sickly deer or elk, avoiding consuming brain or spinal cord tissues, minimizing the handling of brain and spinal cord tissues, and wearing gloves when field-dressing carcasses.

According to Abrams, "The 2006-2007 FoodNet population survey provides useful information should foodborne prion infection become an increasing public health concern in the future. The data presented describe the prevalence of important behaviors and their associations with demographic characteristics. Surveillance of BSE, CWD, and human prion diseases are critical aspects of addressing the burden of these diseases in animal populations and how that may relate to human health."

The article is authored by Joseph Y. Abrams, MPH; Ryan A. Maddox, MPH; Alexis R Harvey, MPH; Lawrence B. Schonberger, MD; and Ermias D. Belay, MD.

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Journal Reference:

1. Joseph Y. Abrams, Ryan A. Maddox, Alexis R Harvey, Lawrence B. Schonberger, Ermias D. Belay. Travel history, hunting, and venison consumption related to prion disease exposure, 2006-2007 FoodNet population survey. Journal of the American Dietetic Association, 2011; 111 (6)

Scientists who examined more than 10,000 chemical compounds during the last year in search of potential new drugs for a group of untreatable brain diseases, are reporting that one substance shows unusual promise. The early positive signs for so-called prion diseases come from research in laboratory mice and cell cultures, they say in a report in ACS' Journal of Medicinal Chemistry.

Adam Renslo and colleagues, who include Nobel Laureate Stanley B. Prusiner, explain that prion diseases include conditions like mad cow disease in animals and Creutzfeldt-Jakob Disease in humans, result from deposits of abnormal prion protein in brain tissue. Prion diseases are invariably fatal and no treatments are yet available.

The scientists describe narrowing their search among the 10,000 candidate drugs to a few dozen of the most promising and then synthesizing new variations of the compounds, termed aminothiazoles. Tests on laboratory mice showed that the new compounds can reach the brain and reach high concentrations when taken orally and do not appear toxic. Tests on prion-infected mouse brain cells showed that the compounds reduced the amount of the abnormal prion protein. The compounds appear to be among the most promising potential treatments for prion diseases yet discovered, the report suggests.

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Journal Reference:

1. Alejandra Gallardo-Godoy, Joel Gever, Kimberly L. Fife, B. Michael Silber, Stanley B. Prusiner, Adam R. Renslo. 2-Aminothiazoles as Therapeutic Leads for Prion Diseases. Journal of Medicinal Chemistry, 2011; 54 (4): 1010 DOI: 10.1021/jm101250y

Researchers at the University of California, San Diego School of Medicine have identified the motors that move non-infectious prion proteins (PrPC) — found within many mammalian cells — up and down long, neuronal transport pathways. Identifying normal movement mechanisms of PrPC may help researchers understand the spread of infectious prions within and between neurons to reach the brain, and aid in development of therapies to halt the transport.

Their study is published in the February 18 edition of the journal Cell.

The small prion protein is found in the cell membrane of brain neurons. The misfolded or infectious form of this protein (also called "scrapie"), is responsible for "mad cow" disease and has also been implicated in Creutzfeldt-Jakob disease in humans. Non-infectious and scrapie forms interact to produce disease; so, in order to help uncover how the infection is spread within and among neuron cells to the brain, the UCSD scientists studied the movement mechanism of normal PrPC in mouse neuronal cells.

"Our work unraveling the normal mechanism of movement of this prion protein will help us understand how the devastating pathogenic versions found in mad cow disease and other prion diseases are formed and transmitted in the brain. Intriguingly, our work may also shed light on what goes wrong in other neurodegenerative diseases such as Alzheimer's disease," said principal investigator Larry Goldstein, PhD, professor of Cellular and Molecular Medicine, Howard Hughes Medical Institute investigator and director of the UC San Diego Stem Cell Program.

It is known that normal prion proteins and infectious prions need to interact in order for prion pathogenesis to occur, though not how or why these interactions occur. Discovering the transport mechanisms of prions is one key to the puzzle of how the two types of proteins interact, and an important question in transport regulation has been how motor activity is controlled in cells.

The prion protein cargo travels on long microtubule tracks along the peripheral and central nervous system nerves toward the terminus, or synapse, in membrane-bound sacs called vesicles. Intracellular transport is often bi-directional, because cargoes regularly reverse their course en route to their final destinations.

The researchers identified the motors driving these vesicles as anterograde Kinesin-1 — which moves only toward the synapse — and dynein, which is retrograde, moving away from the synapse. These two motor proteins assemble on the PrPC vesicles to "walk" them back and forth along the microtubules.

Secondly, they discovered that the back and forth cargo movement is modulated by regulatory factors, rather than by any structural changes to the motor-cargo associations. The study data show that the activity of Kinesin-1 and dynein are tightly coupled, with PrPC vesicles moving at different velocities and for varied lengths along axons. However, the type and amounts of these motor assemblies remain stably associated with stationary as well as moving vesicles, and normal retrograde transport by Kinesin-1 is independent of dynein-vesicle attachment.

The UCSD study of the mechanisms behind normal vesicle movement along the axons in mouse cells might also shed light on other neurodegenerative disease. While Alzheimer's is not generally considered an infectious disease like mad cow disease, emerging data suggest that Tau, amyloid-beta, and alpha-synuclein — proteins implicated in Alzheimer's and Parkinson's disease — have self-propagating fibril structures with prion-like characteristics.

"Whether these toxic molecules spread along neuronal transport pathways in ways similar to the normal prion protein is unknown," said first author Sandra E. Encalada, PhD, of the UCSD Department of Cellular and Molecular Medicine. "But characterization of these normal mechanisms might lead to a way to control movement of intracellular aggregates, and perhaps to therapies for many neurodegenerative diseases."

Additional contributors to the study include Lukasz Szpankowski, of the UCSD bioinformatics graduate program and the Howard Hughes Medical Institute, and Chun-hong Xia, UCSD Department of Cellular and Molecular Medicine, now at UC Berkeley.

The study was supported in part by the National Institutes of Health's National Institute on Aging.

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Journal Reference:

1. Sandra E. Encalada, Lukasz Szpankowski, Chun-Hong Xia and Lawrence S. Goldstein. Stable Kinesin and Dynein Assemblies Drive the Axonal Transport of Mammalian Prion Protein Vesicles. Cell, Volume 144, Issue 4, 18 February 2011, Pages 551-565 DOI: 10.1016/j.cell.2011.01.021

Transmission of prion brain diseases such as bovine spongiform enecephalopathy (BSE) — also known as mad cow disease — and human variant Creutzfeldt-Jakob disease (vCJD) is generally attributed to the consumption of the brain or organ meat of infected animals but new research demonstrates lambs exposed to milk from prion-infected sheep with inflamed mammary glands can develop prion disease as well. The research, which is published in the January 2011 issue of the Journal of Virology, has major implications for human and livestock health.

"Prions cause devastating, ultimately fatal infections in humans," says corresponding author Christina Sigurdson of the University of California, San Diego School of Medicine. "This study is the first demonstration of prions from an inflamed organ being secreted, and causing clinical symptoms in a natural host for prion disease."

Recent research had suggested that human-to-human transmission of prions has occurred via blood transfusions, "underscoring the importance of understanding possible transmission routes," the researchers write. The misfolded prions that cause vCJD in humans, and BSE in cattle — which can be transmitted to humans — commonly accumulate in lymphoid tissues before invading the central nervous system, where they wreak their deadly effects. Inflammation can cause lymphoid follicles to form in other organs, such as liver and kidney, which leads prions to invade organs that normally do not harbor infection. In recent research, this team, led by Ciriaco Ligios of the Istituto Zooprofilattico Sperimentale in Sardinia, Italy and Adriano Agguzi at the University of Zurich, Switzerland, reported sheep with misfolded prions in inflamed mammary glands, also known as mastitis, raising concerns that prions could be secreted into milk.

In the new research, the team infected sheep with a common retrovirus that causes mastitis, and misfolded prions. They bred the sheep, in order to stimulate the females to produce milk, which they then collected and fed to lambs that had never been exposed to prions. The lambs developed prion disease after only two years, a speed which surprised the researchers, and "suggested that there was a high level of prion infectivity in milk," says Sigurdson.

The research raises several disturbing possibilities.

• A common virus in a sheep with prion disease can lead to prion contamination of the milk pool and may lead to prion infection of other animals.
• The same virus in a prion-infected sheep could efficiently propagate prion infection within a flock, through transmission of prions to the lambs, via milk. This might be particularly likely on factory farms, where mastitis may be common, and could occur in goats as well as sheep.
• Humans with variant Creutzfeldt-Jakob disease (vCJD) might accumulate prions in inflamed organs, and could also secrete prions.

However, "This work cannot be directly extrapolated to cattle," says Sigurdson. She says that BSE prions do not accumulate to detectible levels in lymphoid organs, and thus would not be expected to accumulate with inflammation. "Nonetheless," she says, "it would be worth testing milk from cattle with mastitis for prions as there may be other cellular sources for prions entry into milk."

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Journal Reference:

1. C. Ligios, M. G. Cancedda, A. Carta, C. Santucciu, C. Maestrale, F. Demontis, M. Saba, C. Patta, J. C. DeMartini, A. Aguzzi, C. J. Sigurdson. Sheep with Scrapie and Mastitis Transmit Infectious Prions through the Milk. Journal of Virology, 2010; 85 (2): 1136 DOI: 10.1128/JVI.02022-10

Scientists from the Florida campus of The Scripps Research Institute have shown that prions, bits of infectious protein that can cause fatal neurodegenerative disease such as bovine spongiform encephalopathy (BSE) or "mad cow disease," have the ability to adapt to survive in a new host environment.

In this regard, although they lack DNA and RNA, they behave much like viruses, producing distinct self-perpetuating structural mutations that provide a clear evolutionary advantage.

The study was published this week in the online Early Edition the journal Proceedings of the National Academy of Sciences.

"We found that when a particular prion strain is transferred from brain cells to a different cell line, its properties gradually change, giving rise to a variant strain that is better adapted to this new cellular environment," said Charles Weissmann, M.D., Ph.D., the head of Scripps Florida's Department of Infectology, who led the study. "If those same prions are subsequently transferred to another cell line, they change again, adapting to these new host cells. And if returned to the brain, the prions gradually regain their original properties. We found physical evidence that, at least in one case, the fold of the prion changed when its properties changed."

Darwinian Evolution Without DNA

These new findings come approximately one year after Weissmann and colleagues published a study in the January 1, 2010 edition of the journal Science that showed that prions were capable of Darwinian evolution.

That earlier study also showed that prions can develop large numbers of mutations and that these mutations can bring about such evolutionary adaptations as drug resistance, a phenomenon previously known to occur only in bacteria and viruses. This study also suggested that the normal prion protein — which occurs naturally in mammalian cells — may prove to be a more effective therapeutic target than its abnormal toxic relation.

"Because prions can adapt to changing environments, it now becomes clear that it will be more difficult than originally thought to find drugs that will work against them," Weissmann said. "But if you could develop a drug that inhibits formation of the normal prion protein, you could, in essence, starve the infectious prions and prevent them from reproducing. This approach to treatment, although technically demanding, can be envisaged because, as we have shown earlier, deprivation of PrP is not detrimental to health — at least to the health of mice."

Folding and Misfolding

Prions, which are composed solely of protein, are classified by distinct strains, characterized by their incubation time and the disease they cause. In addition to BSE/mad cow disease in cattle, diseases caused by prions include scrapie in sheep, chronic wasting disease in deer, and variant Creutzfeldt-Jakob disease in humans. Prions have the ability to reproduce, despite the fact that they contain no nucleic acid genome.

Mammalian cells normally produce cellular prion protein or PrP^C. During infection, abnormal or misfolded protein — known as PrP^Sc — converts the normal host prion protein into its toxic form by changing its conformation or shape. The end-stage consists of large sheets (polymers) of these misfolded proteins, which causes massive tissue and cell damage.

"The infectious prion protein can fold in different ways, and depending on the fold, a different prion strain results," Weissmann said. "As long as prions are maintained in the same host, they retain their characteristic fold, so that strains breed true."

When prions multiply, however, that fold is not always reproduced correctly, so a prion population contains many variants, albeit at low levels.

The new study found that when a prion population is transferred to a different host, one of the variants may replicate faster — an evolutionary advantage — and become the dominant strain. This new population also contains variants, one of which may be selected over others when transferred to a different host.

"The result is that prions, although devoid of genetic material, behave similarly to viruses and other pathogens, in that they can mutate and undergo evolutionary selection," Weissmann said. "They do it by changing their fold, while viruses incur changes in their nucleic acid sequence."

Diverse Yet Related

The new study suggests that prion populations constitute a "quasi-species" similar in nature to RNA viruses and retroviruses, such as flu viruses and HIV.

The idea of a quasi-species was first conceived by Manfred Eigen, a German biophysicist who won the Nobel Prize in Chemistry in 1967. Basically, a quasi-species is a complex, self-perpetuating population of diverse and related entities that act as a whole. It was Weissmann, however, who in 1978 provided the first confirmation of the theory through the study of a particular bacteriophage — a virus that infects bacteria — while he was director of the Institut für Molekularbiologie in Zürich, Switzerland.

But that's where the comparison ends, Weissmann said.

"The fact that they behave like viruses doesn't mean they're anything like a virus," he said. "A bicycle is like a car in that it gets you from one place to the other, but they're not the same. The end effect is the same, however. Prions and viruses are both able to change their structure to survive."

The first author of the study is Sukhvir P. Mahal of Scripps Research. Other authors include Shawn Browning, Jiali Li, and Irena Suponitsky-Kroyter, also of Scripps Research.

The study was supported by the National Institutes of Health and the Alafi Family Foundation.

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Journal Reference:

1. S. P. Mahal, S. Browning, J. Li, I. Suponitsky-Kroyter, C. Weissmann. Transfer of a prion strain to different hosts leads to emergence of strain variants. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1013014108

— In a new research report in the December 2010 print issue of The FASEB Journal, scientists found that a protein our body uses to break up blood clots speeds up the progress of prion diseases. This substance, called plasminogen, is a new drug target for prion diseases in both humans and animals.

"I hope that our study will aid in developing therapy for prion diseases, which will ultimately improve the quality of life of patients suffering from prion diseases," said Chongsuk Ryou, Ph.D., a researcher involved in the work from the University of Kentucky in Lexington. "Since prion diseases can lay undetected for decades, delaying the ability of the disease-associated prion protein to replicate by targeting the cofactor of the process could be a monumental implication for treatment."

To make this discovery, the researchers used simple test tube reactions to multiply disease-associated prion proteins. The reactions were conducted in the presence or absence of plasminogen. They found that the natural replication of the prions was stimulated by plasminogen in both human and animal cells.

"Rogue prions are one of nature's most interesting, deadly and least understood biological freakshows," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "They are neither virus nor bacteria, but they kill or harm you just the same. By showing how prions hijack our own clot-busting machinery, this work points to a new target for anti-prion therapy."

According to the U.S. National Institute of Allergy and Infectious Diseases, prion diseases are a related group of rare, fatal brain diseases that affect animals and humans. The diseases are characterized by certain misshapen protein molecules that appear in brain tissue. Normal forms of these prion protein molecules reside on the surface of many types of cells, including brain cells, but scientists do not understand what normal prion protein does.

On the other hand, scientists believe that abnormal prion protein, which clumps together and accumulates in brain tissue, is the likely cause of the brain damage that occurs. Scientists do not have a good understanding of what causes the normal prion protein to take on the misshapen abnormal form. Prion diseases are also known as transmissible spongiform encephalopathies, and include bovine spongiform encephalopathy ("mad cow" disease) in cattle; Creutzfeldt-Jakob disease in humans; scrapie in sheep; and chronic wasting disease in deer and elk. These proteins may be spread through certain types of contact with infected tissue, body fluids, and possibly, contaminated medical instruments.

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Journal Reference:

1. C. E. Mays, C. Ryou. Plasminogen stimulates propagation of protease-resistant prion protein in vitro. The FASEB Journal, 2010; DOI: 10.1096/fj.10-163600

Pathological protein deposits linked to Alzheimer's disease and cerebral amyloid angiopathy can be triggered not only by the administration of pathogenic misfolded protein fragments directly into the brain but also by peripheral administration outside the brain.

This is shown in a new study done by researchers at the Hertie Institute of Clinical Brain Research (HIH, University Hospital Tübingen, University of Tübingen) and the German Center for Neurodegenerative Diseases (DZNE), published in Science.

Alzheimer's disease and a brain vascular disorder called cerebral beta-amyloid angiopathy are characterized by the accumulation of a protein fragment known as Aβ. In Alzheimer´s disease, misfolded Aβ is deposited mainly in so-called amyloid plaques, whereas in cerebral beta-amyloid angiopathy, the Aβ protein aggregates in the walls of blood vessels, interfering with their function and, in some cases, causing them to rupture with subsequent intracerebral bleeding.

In 2006, scientists in Tübingen, led by Mathias Jucker, reported that injection of dilute extracts from Alzheimer's disease brain tissue, or from Aβ-laden mouse brain tissue, into the brains of transgenic mice (genetically modified to produce the human form of Aβ) stimulated Aβ aggregation within the mouse brain (Science 313: 1781-4, 2006).

In the current Science study, Professor Jucker and first author Yvonne Eisele, together with their research team (HIH, University of Tübingen, DZNE) and colleagues Matthias Staufenbiel (Novartis), Mathias Heikenwälder (University of Zürich), and Lary Walker (Emory University, Atlanta) report that Aβ deposition can be induced in the transgenic mouse brain by the intraperitoneal administration of mouse brain extract containing misfolded Aβ. This induced Aβ deposition was primarily associated with the vasculature, but was also evident as amyloid plaques between nerve cells. The time needed to induce amyloid deposition in the brain was much longer for peripheral as compared to direct brain administration. In both cases, the induced amyloid deposition also triggered several neurodegenerative and neuroinflammatory changes commonly observed in the brains of patients with Alzheimer´s disease and cerebral beta-amyloid angiopathy.

"The finding that mechanisms exist allowing for the transport of Aβ aggregates from the periphery to the brain raises the question of whether protein aggregation and propagation, which may also be involved in other neurodegenerative brain diseases, can be induced by agents originating in the periphery," points out Professor Jucker. The present findings provide new clues on pathogenetic mechanisms underlying Alzheimer's disease; further investigation will likely lead to new strategies for prevention and treatment.

While this molecular principle of induced protein aggregation bears similarities to that of prion diseases, the latter, which include bovine spongiform encephalopathy (BSE), can also be initiated by introducing prions at sites peripheral to the brain. The present study shows that this is not a characteristic unique to prion diseases, as has been assumed so far. Despite this remarkable observation and the apparent mechanistic similarities between Alzheimer´s and prion diseases, there is no evidence that Alzheimer's disease or cerebral amyloid angiopathy is transmitted between mammals or humans in the same manner as prion diseases.

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Journal Reference:

1. Y. S. Eisele, U. Obermuller, G. Heilbronner, F. Baumann, S. A. Kaeser, H. Wolburg, L. C. Walker, M. Staufenbiel, M. Heikenwalder, M. Jucker. Peripherally Applied Aβ-Containing Inoculates Induce Cerebral β-Amyloidosis. Science, 2010; DOI: 10.1126/science.1194516

The eyes of sheep infected with scrapie — a neurological disorder similar to mad cow disease — return an intense, almost-white glow when they're hit with blue excitation light, according to a research project led by Iowa State University's Jacob Petrich.

The findings suggest technologies and techniques can be developed to quickly and noninvasively test for transmissible spongiform encephalopathies, progressive and fatal neurological diseases such as mad cow disease in cattle and Creutzfeldt-Jakob disease in humans. Petrich, in fact, is working to develop a testing device.

The findings were published earlier this year in the journal Analytical Chemistry. The project was supported by a grant from the U.S. Department of Defense.

The research is the result of an accidental discovery while Petrich and his collaborators were developing a fluorescence spectroscopy device that's now used in slaughterhouses to test livestock carcasses for feces and possible E. coli contamination.

"One day we were testing the apparatus by shining light on the carcass and we saw the spinal cord glow — it fluoresced," said Petrich, professor and chair of Iowa State's chemistry department. "We saw the spinal cord through the skin. The light was pretty intense. It was an amazing result."

That sparked some new thinking: Maybe fluorescence technology could be used to test animals for transmissible spongiform encephalopathies such as bovine spongiform encephalopathy — what's often called mad cow disease. To reduce the risk of human exposure to the diseases, the brains and spinal cords of animals are removed during slaughter and processing. But there is no quick test to identify animals with the diseases.

And so Petrich and a team of researchers began studying the feasibility of a fluorescence test. The team included Ramkrishna Adhikary, an Iowa State graduate student in chemistry; Prasun Mukherjee, a former Iowa State graduate student and current post-doctoral associate in chemistry at the University of Pittsburgh; Govindarajan Krishnamoorthy, a former Iowa State post-doctoral research associate and current assistant professor of chemistry at the Indian Institute of Technology Guwahati; Robert Kunkle of the U.S. Department of Agriculture's National Animal Disease Center in Ames; Thomas Casey of the National Animal Disease Center; and Mark Rasmussen of the U.S. Food and Drug Administration's Center for Veterinary Medicine in Laurel, Md.

The researchers collected 140 eyeballs from 73 sheep. Thirty five of those sheep were infected with scrapie; 38 were not. The researchers took fluorescence readings from various parts of the eyes of all the sheep.

"The bottom line is the scrapie-positive retinas fluoresced like crazy," Petrich said. "And the scrapie-negative ones did not."

A previous study published in the journal Veterinary Pathology reported that the function and structure of retinas are altered in cattle infected with transmissible mink encephalopathy. Members of that study team included Iowa State researchers M. Heather West Greenlee, an associate professor of biomedical sciences in the College of Veterinary Medicine; Justin Greenlee, a collaborator assistant professor of biomedical sciences; and Juergen Richt, a collaborator associate professor of veterinary microbiology and preventive medicine.

Other studies have reported that lipofuscin, an intracellular fluorescent pigment, accumulates in the eyes of animals infected with the neurological diseases. Petrich and his team attribute the glow from scrapie-positive retinas to the elevated levels of lipofuscin.

Whatever the cause, Petrich said it's clear there are distinct differences in the fluorescence and spectroscopic signatures of retinas from sheep that were naturally infected with scrapie and those that were not. And so he and his research team think there's great promise for a diagnostic test based on that discovery.

That has Petrich starting to develop a device (he likes to call it a "gizmo") that could be used in meat plants to test the retinas of animals for signs of neurological diseases. He expects it will take several years to develop, build and test a useful device.

"What I like about this is it's really simple," Petrich said. "It's light in and light out."

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Journal References:

1. Ramkrishna Adhikary, Prasun Mukherjee, Govindarajan Krishnamoorthy, Robert A. Kunkle, Thomas A. Casey, Mark A. Rasmussen, Jacob W. Petrich. Fluorescence Spectroscopy of the Retina for Diagnosis of Transmissible Spongiform Encephalopathies. Analytical Chemistry, 2010; 82 (10): 4097 DOI: 10.1021/ac100179u
2. J. D. Smith, J. J. Greenlee, A. N. Hamir, J. A. Richt, M. H.W. Greenlee. Retinal Function and Morphology Are Altered in Cattle Infected with the Prion Disease Transmissible Mink Encephalopathy. Veterinary Pathology, 2009; 46 (5): 810 DOI: 10.1354/vp.08-VP-0206-W-FL