Al zheimer’s Prion Connection | July 2, 2012 Issue - Vol. 90 Issue 27 | Chemical & Engineering News
 
 
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Volume 90 Issue 27 | pp. 24-26
Issue Date: July 2, 2012

Alzheimer’s Prion Connection

Scientists debate public health impact of the prionlike behavior of neurodegenerative proteins
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE
Keywords: Alzheimer’s, prions, mad cow disease, misfolded proteins, Parkinson’s, amyloid
[+]Enlarge
BAD INFLUENCE
Like prions, proteins associated with other neurodegenerative diseases can misfold and then recruit similar proteins to do the same, eventually forming harmful aggregates in the brain such as plaques (~50 µm in diameter), tangles (~10–40 µm), and Lewy bodies (~5–10 µm).
Credit: Adapted from Science
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BAD INFLUENCE
Like prions, proteins associated with other neurodegenerative diseases can misfold and then recruit similar proteins to do the same, eventually forming harmful aggregates in the brain such as plaques (~50 µm in diameter), tangles (~10–40 µm), and Lewy bodies (~5–10 µm).
Credit: Adapted from Science

Ask a science-savvy person what comes to mind when faced with the term “prion,” and the answer will likely be “mad cow disease.” The malady, known in scientific circles as bovine spongiform encephalopathy, famously broke out in the U.K. during the 1980s, infecting at least 180,000 cattle and leading to the slaughter of millions of others because of its infectivity.

Unlike many transmissible diseases, mad cow is not caused by a bacterium or a virus. Rather, the infectious agent is a prion, a misfolded protein that can wreak havoc in the brain. After appearing inside the body, a prion slowly recruits similar proteins to misfold, clump, and clog the nerve-cell network.

Prior to the 1980s, scientists found that prions could pass from person to person under unusual circumstances, such as implantation with infected tissue. But when researchers later discovered that the proteins could cause variant Creutzfeldt-Jakob disease in humans who ate infected beef, prions cemented their reputation as bad actors.

So when a scientist goes on record saying that the signature protein of Alz­heimer’s disease, amyloid-β, behaves like a prion and therefore has the potential to be infectious, people take notice—and get a little worried.

That’s exactly what happened late last year after Claudio Soto, a neurologist at the University of Texas Medical School, in Houston, published a study demonstrating that “seed” particles of misfolded amyloid-β from humans can cause damage in the brains of mice (Mol. Psychiatry, DOI: 10.1038/mp.2011.120). When Soto and his group took brain tissue from a deceased Alzheimer’s patient and injected it into the rodents’ brains, they observed amyloid clumps accumulate and spread.

After the paper’s publication, media outlets such as Fox News featured stories with sensational headlines like, “Can You ‘Catch’ Alzheimer’s Disease?”

Soto’s findings caused a stir, even though they were not the first to show similarities between conventional misfolded neuro­degenerative proteins and prions. Over the past decade, laboratory evidence has been mounting that both amyloid-β and tau protein, another macromolecule that misfolds and tangles up in the brains of Alzheimer’s patients, behave like prions. Researchers have also seen similar mechanisms of seeding, recruitment, and spreading for α-synuclein, the main protein player involved in Parkinson’s disease.

But the question is, if amyloid-β, tau, and α-synuclein act like prions in the lab, can these misfolded proteins pass from person to person, too?

All of the neuroscientists C&EN interviewed agree that these neurodegenerative proteins are transmissible in the laboratory. But injecting animals with brain tissue is a far cry from what goes on in the real world. No firm evidence exists that the diseases caused by misfolded amyloid-β and its kin are infectious outside the lab, experts say.

On the other hand, few are willing to rule out the possibility that Alzheimer’s might be transmitted from person to person. Like prion diseases, neuroscientists say, Alzheimer’s and other neurodegenerative diseases would not be spread via casual contact, but perhaps via other routes such as blood transfusion or neurosurgery. Still, some in the research community object to labeling amyloid-β and other misfolded neurodegenerative proteins as prions, and thereby scaring the public, until more is known.

The idea that misfolded proteins involved in neurodegeneration, such as amyloid-β and tau, might be transmissible was born in the 1970s from studies of prions. But it was famously revisited in the early 1990s, says Virginia M.-Y. Lee, a pathologist at the University of Pennsylvania Perelman School of Medicine. That’s when Heiko Braak, an anatomist now at the University of Ulm, in Germany, studied the pattern of protein aggregates distributed in the brains of Alzheimer’s patients. Looking at a multitude of autopsied brains, Braak observed that both amyloid plaques and tau tangles moved into specific regions of the brain during different stages of the disease, increasing in density with Alzheimer’s progression.

These “tantalizing” results, Lee says, “suggested that there is a stereotypical manner in which Alzheimer’s pathology spreads” in the brain.

To uncover the mechanism of this patterned spread, though, scientists would first need proper tools—engineered nerve cells and animals—to reproduce and then study the process, Lee says. These tools became available over time.

In 2000, a team led by Lary C. Walker, a neuroscientist now at Emory University, possessed one of the first mice genetically engineered to produce and accumulate in their brains the amyloid-β plaques associated with human Alzheimer’s. “Because the idea had been floating around that Alzheimer’s and other diseases might have some similarities to prion diseases, we decided to test the theory out,” Walker says.

The team injected brain tissue from Alzheimer’s patients into the brains of three-month-old engineered mice. Typically, these mice would not begin developing amyloid plaques until nine months of age. Walker’s team showed that the injections accelerate disease progression: Five months afterward, the rodents already carried the brain plaques (J. Neurosci.2000,20, 3606).

Fast-forward to 2011, when Soto carried out similar experiments with a different type of mouse. Soto’s rodents were also engineered to express the protein building blocks necessary to make human amyloid-β, but the mice were designed not to accumulate plaques during their normal two- to three-year life spans.

About 280 days after injecting Alzhei-mer’s brain tissue, however, the research team observed the protein aggregates in the rodents’ brains. About 580 days afterward, the brains of nearly 100% of the mice were riddled with amyloid plaques.

Walker’s studies were seminal, Soto says. “But we wanted to start with an animal that is ‘normal,’ one that would never develop the disease unless infected,” he says. That’s more akin to what happens in prion diseases, he adds.

Similar experiments have also been carried out for tau protein and α-synuclein. In fact, Penn’s Lee has been instrumental in demonstrating that α-synuclein behaves like a prion with respect to its transmissibility. Her group added synthetic α-synuclein fibrils to mouse nerve cells carrying a normal level of native α-synuclein. The researchers observed those fibril seeds gain access to the cells—although the entrance mechanism is not yet known, she says—and then spread through the neurons. As the fibrils spread, they formed aggregates usually found in the brains of Parkinson’s patients, called Lewy bodies (Neuron, DOI: 10.1016/j.neuron.2011.08.033).

“Once you have a seed of misfolded species inside the cell,” Lee says, “it can corrupt the native protein inside, causing it to adopt the bad conformation.”

Lee and her group have also shown that this process can happen in a mouse’s brain seeded with synthetic α-synuclein fibrils. About 100 days after the researchers injected the brains of two- to three-month-old mice with misfolded synthetic fibrils, Lewy bodies started developing (J. Exp. Med., DOI: 10.1084/jem.20112457). The genetically engineered mice they used typically accumulate aggregates no earlier than eight months of age.

Demonstrating protein transmission with synthetic seeds is important, Lee says, because when the fibrils are derived from brain tissue “you can never be certain that there aren’t other cofactors in there that work together to cause spreading.” In other words, “the best way to prove that the fibrils are wholly responsible for the spreading pathology,” she adds, “is to inject synthetic versions by themselves.”


Researchers hadn’t been able to get experiments with synthetic amyloid-β to work, and thus prove its seed status in Alzheimer’s, until two weeks ago. That’s when a team led by Kurt Giles and Stanley B. Prusiner of the University of California, San Francisco, published an article in Proceedings of the National Academy of Sciences USA (DOI: 10.1073/pnas.1206555109) that did just that: The researchers successfully accelerated the formation of amyloid plaques in the brains of mice by injecting the rodents’ brains with misfolded synthetic amyloid-β particles.

Asked how he and Prusiner, a 1997 Nobel Prize winner for his research on prions, succeeded where others had failed, Giles says others might not have used properly misfolded amyloid-β seeds or might not have waited long enough for plaques to start forming before looking at rodents’ brains.

To address the latter problem, Giles and Prusiner used a technique called bioluminescence imaging. They genetically engineered mice so that the rodents’ brains fluoresce when amyloid plaques start to build up. Giles explains that, with the imaging technique, the team can see the fluorescence through the rodents’ skulls. “Then we can say, ‘Right, we know that we have disease progression, so now’s the time to take the brains out and analyze them,’ ” he adds.

[+]Enlarge
STAGES OF DISEASE
Misfolded protein clumps such as amyloid plaques (top) and tau tangles (bottom) spread through the brains of Alzheimer’s patients in a specific pattern (left to right). Darker shading indicates increased clump density over time.
Credit: Ann. Neurol.
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STAGES OF DISEASE
Misfolded protein clumps such as amyloid plaques (top) and tau tangles (bottom) spread through the brains of Alzheimer’s patients in a specific pattern (left to right). Darker shading indicates increased clump density over time.
Credit: Ann. Neurol.

Taken together, these results point to amyloid-β and other neurodegenerative proteins as behaving like prions, says Neil R. Cashman, a neurologist at the University of British Columbia, in Vancouver. “It’s becoming a widely accepted idea,” he adds. “But it’s also opening a Pandora’s box.”

Only one in a million people in the U.S. die of a prion disease each year, according to the Centers for Disease Control & Prevention. Those diseases are never transmitted from person to person via casual, or even intimate, contact, Cashman says. But people have contracted prion diseases via tissue implants, tainted neurosurgical instruments, or blood transfusions.

So far, there’s been no evidence of infection via any of those routes for neurodegenerative proteins such as amyloid-β, but it’s something to keep an eye on, Cashman adds. “We have all been of the opinion that there is no public health risk” in the spreading of these misfolded proteins, he says, but “the recent experimental data make it a valid concern that deserves further research.”

Some infectivity research has already been carried out. In 2009, Mathias Jucker of Tübingen University, in Germany, along with Emory’s Walker, implanted stainless steel wires coated with amyloid-β seed particles into the brains of mice. The wires were meant to simulate the use of steel instruments in neurosurgery.

Plaques formed in the tissue surrounding the wire and, to a lesser extent, elsewhere in the rodents’ brains. Heating the wires to 95 °C before implantation did not prevent the misfolded proteins from spreading, but plasma sterilization did (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0903200106).

UT Houston’s Soto has also been making some noise recently about unpublished work from his group showing that amyloid plaque formation can be triggered in the brains of mice through blood transfusion. Cases of prion diseases transmitted to others by infected blood donors are known, Soto says, “so we wanted to look at whether this process is applicable to neurodegenerative diseases as well.” Although he won’t yet discuss the details, he says “the results seem to be positive” and suggest that amyloid-β seeds can cross the blood-brain barrier.

Knowing that amyloid-β and similar proteins act like prions, researchers are left wondering why no one has recorded a case of the proteins passing from person to person. On the basis of laboratory results, “we all think they should be infectious,” Jucker says, “but there’s no evidence.” He and others are awaiting Soto’s blood transfusion results to be published before further considering the possibility.

Soto and Cashman say evidence for infectivity may be lacking because proper epidemiological studies have just not been performed yet. “Neurodegenerative disease symptoms take a long time to show up,” Soto says. “A person might be exposed one day to a misfolded protein but show signs of the disease several decades afterward. It would be difficult to track.”

According to Cashman, one test of the infectivity hypothesis might be to examine blood transfusions from elderly donors to young recipients. “If the incidence of nongenetic Alzheimer’s increased 30 years after the transfusions,” he says, “then we might get a hint that these diseases are transmissible.”

Another reason there might be a lack of evidence that these neurodegenerative proteins are infectious, Emory’s Walker says, is that their misfolded forms just aren’t as sturdy as prions. “Prions are remarkably resistant to destruction,” he says. “It’s likely that a lot of these other proteopathic seeds are much less so and are perhaps more easily degraded by enzymes in the body.” That’s an idea that will need to be investigated, he adds.

Until researchers know the answers to these questions, though, “should we be scaring people with a possibility that may not be a problem at all?” Walker asks. “That’s the essence of the controversy going on in the field right now.” On the other hand, he adds, “it would be a mistake to ignore something that is a potential health risk.”

In the meantime, some in the field are calling for researchers to be careful about how they discuss their work with the media and public. In a recent article, John Hardy and Tamas Revesz of University College London called on fellow scientists to avoid using the term prion to describe amyloid-β and similar proteins associated with neurodegenerative disease (N. Engl. J. Med., DOI: 10.1056/NEJMcibr1202401).

“We’re in danger of devaluing the word ‘ prion, ’ ” Hardy says. Prions can be highly infectious, particularly among animals. For instance, studies have shown that prions are so robust, they stick around in soil years after flocks of infected sheep roamed on top of it, Hardy says. That situation is hardly comparable with the one for amyloid-β, he argues. Prions and these other proteins may spread by similar mechanisms, Hardy says, but nothing like the devastating mad cow disease transmission of the 1980s has ever been observed for Alzheimer’s. “It’s irresponsible to stir up that fear,” he says.

Despite the concerns this current wave of research has dredged up, Penn’s Lee and others see a silver lining. What these results provide the research community, Lee says, are potential new drug targets at which to block progression of these devastating neurodegenerative diseases. “This really creates new opportunities,” she says, “and we’re very excited about it.”

 
Chemical & Engineering News
ISSN 0009-2347
Copyright © American Chemical Society
Comments
Josef Hlasny,DVM,PhD  (August 1, 2012 5:53 AM)
Acording to my opinion; what is the common denominator of the neurodegenerative diseases (mad cow disease…) , including Alzheimer's disease? This was 11 years ago ( March 2001), when I published (in Czech) an alternative theory ( BSE ammonia- magnesium theory), where the main role of NMDA receptors was described. In addition, in scientific literature there was described the effect of drugs, in Alzheimer's disease in humans, on the principle of control hyperfunction of NMDA receptors, which is consistent with my BSE alternative theory of BSE. See more about the Nameda; A medication known as Namenda® (memantine), an N-methyl D-aspartate (NMDA) antagonist, is prescribed to treat moderate to severe Alzheimer’s disease.
The neurodegenerative diseases, occurred to a greater extent, only in ruminants (BSE), because only in them, magnesium is not absorbed in the intestine, but in the rumen. The excess of protein-nitrogen in the rumen decreases absorption of magnesium. Most suffer with magnesium deficiency, high yielding dairy cows, in which high milk production leads to the dysbalancy between calcium and magnesium. Prolonged magnesium deficiency leads to an excess of calcium in animal tissues, and NMDA receptor hyperfunction. From the period around 1985, new dietary standards are known in dairy cows (eg, NRC 1985…), which began recommending high concentration of protein in the feed rations of cows.
More details about altered neuronal calcium homeostasis and NMDA receptor antagonists action in AD was recently published by French scientists (BORDJI et al. 2010 ).
They found that altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of β-amyloid (Aβ), and contributing to the initiation of Alzheimer’s disease (AD). A linkage between excessive glutamate N-methyl-d-aspartate (NMDA) receptor activation and neuronal Aβ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR leads to neuronal Aβ release, representing a causal risk factor for developing AD (BORDJI et al 2010).
For one decade, several studies provided evidence that NMDAR activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDAR activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer’s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia (BORDJI et al 2011).
Putting into the practical conditions, researchers have found that a new highly absorbable form of magnesium called magnesium-L-threonate concentrates more efficiently in the brain, rebuilds ruptured synapses, and restores the degraded neuronal connections observed in Alzheimer's disease and other forms of memory loss (SLUTSKY et al. 2010). In experimental models, magnesium-L-threonate induced improvements of 18% for short-term memory and 100% for long-term memory. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced.
I worked in the USA almost one year- West Virginia University (1991, Morgantown). There I obtained a lot of information from scientific journals (in former Czechoslovakia it was not possible), what I used to create an alternative theory of the origin and the spread of mad cow disease (BSE). Relevant findings I have published 11 years ago in Czech (March 2001) and in English (May 2002; Netherlands, International Journal "Feed Mix"; www.warmwell.com/lone_voices_in_the_bse_debate[1].pdf ). Later, in August 2006, I published own website, see; www.bse-expert.cz . Since then I pointed my website in the order of hundreds of magazines around the world, especially in the U.S.. See some of them, for example on Google; www.google.com/search?q=hlasny+bse+expert&hl=cs&lr=&start=0&sa=N&filter=0 . In 2008, I repeatedly visited the USA, it was about the occasion of my presentation in Vancouver, Canada (July 2008; 29th World Veterinary Congress; Neurodegenerative Diseases and Schizophrenia as a Hyper or Hypofunction of the NMDA Receptors (www.bse-expert.cz/pdf/Veter_kongres.pdf ).
According to my theory, the origins of the neurodegenerative diseases may lie in chronic magnesium deficiency coupled with a high protein intake. So defective prions are markers of the diseases rather than the cause and BSE can be a naturally occurring disease, not an infectious disease. WHY?
Because, about the BSE/ vCJD diseases; this was never justified scientifically! It was pure, math-model-driven science fiction. But it was pushed very vigorously by the British science establishment, which has never confessed to its errors... See more about the; BSE/ vCJD mathematical- models, see recent large three comments (February 2010) in Telegraph.co.uk (www.telegraph.co.uk/health/healthnews/7168326/Does-vCJD-still-pose-a-major-public-health-threat.html ).
However, well-known circumstances can be show (as a detective story); in documenting the first case of disease transmission, by blood transfusion. For more informations see my other large comments (January 12, 2011) in Western Star (www.thewesternstar.com/News/Canada%20-%20World/Business/1969-12-31/article-2095060/Womans-death-in-northern-Italy-is-nations-2nd-fatal-case-of-mad-cow-disease/1 ). At the present time I will complete my website to the final version, so it would be clear among other things, that mad cow disease has never been and is not an infectious disease. Among other things, there much contributed recent research (2011/12) about the Alzhemeir´s disease.
G. Balachandar  (January 13, 2013 4:17 PM)
Dear Dr.Wolf,
I am a Gastroenterologist in Plano,a suburb of Dallas, Texas. My son who is a High School student in Plano is doing a research project about simulating the relationship between Tau Protein hyperphosphorylation and development of Alzheimer's disease.

In order to conduct his simulation he needs the following data:
1. In http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1001101 , Figure 3 shows the Clinical Dementia Rating sum of boxes (SB-CDR) over time. However, he was not able to find how the SB-CDR is calculated and how it is related to accumulation of hyperphosphorylated tau.
2. What are the probabilities of the occurences of various SNPs associated with AD (rs1868402, rs3785883, etc) and these SNPs' different tendencies to result in hyperphosphorylated tau?
3. What is the rate of accumulation of hyperphosphorylated tau with respect to time?
The project is to simulate the rate of accumulation of hyperphosphorylated tau proteins as a result of different SNPs, particularily rs1868402 and rs3785883. He will map out a portion of the brain to simulate the aggregation of the hyperphosphorylated protein over time.

He needs only the data. He does not need any patient names or any private information. Would you be able to provide this data from the research/clinical base you have at the Medical School? Or can you direct me to any faculty member who has an interest in this topic? I sincerely appreciate your help in this matter. You may contact me via email or my cell phone 214-734-9901

Gowri Balachandar, M.D.
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