Axonal prion protein is required for peripheral myelin maintenance

Juliane Bremer, Frank Baumann, Cinzia Tiberi, Carsten Wessig, Heike Fischer, Petra Schwarz, Andrew D Steele, Klaus V Toyka, Klaus-Armin Nave, Joachim Weis, et al.

출처 : Nature Neuroscience (24 January 2010) doi:10.1038/nn.2483 Article

연구팀의 연구결과는 [네이처 신경과학] 2010년 1월 24일자에 게재되었습니다.

이 기사에는 스위스 출신의 세계적인 프리온 연구의 권위자 아드리아노 아구치 박사의 20년에 걸친 프리온 연구에 대해서 간단하게 소개되어 있기도 합니다.

최근 과학자들은 프리온 단백질이 후각이나 시각과 관련이 있다는 연구결과를 발표한 바 있으며, 프리온 단백질이 알츠하이머병이 발생하지 않도록 보호해주는 기능을 한다는 연구결과 등을 발표하기도 했습니다.

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Healthy prions protect nerves

Alison Abbott

출처 : Nature News (24 January 2010) doi:10.1038/news.2010.29 News
http://www.nature.com/news/2010/100124/full/news.2010.29.html

The proteins that can cause CJD have a vital role in the nervous system.

Alison Abbott

Prion proteins help to keep nerve cells well insulated.STEVE GSCHMEISSNER / SPL

After 20 years of research, scientists believe they have finally uncovered the normal function of prion proteins, which can cause deadly illnesses such as Creutzfeldt–Jakob disease (CJD) if they become incorrectly folded.

An international team of neuroscientists reports that, in mammals, the mysterious proteins help to maintain the myelin sheath that protects the body’s nerves.

“This opens a new door to studying some of the many common neuropathy disorders — which lead to weakness or loss of sensitivity of limbs — where we don’t know the cause,” says prion expert Simon Mead at University College London’s Institute of Neurology.

The authors suspect that their finding also applies to brain neurons. If so, this would have implications for treating deadly CJD and other transmissible spongiform encephalopathies. It could also offer a new way of looking at multiple sclerosis, an incurable disease caused by demyelination of nerves in the brain and spinal cord. The work is published online in Nature Neuroscience today¹.

Long search

Several functions have been proposed for prions during the past couple of decades, but none has survived close scrutiny.

“The first mouse with knocked-out prion genes was made back in 1991,” says Adriano Aguzzi at the University Hospital of Zurich in Switzerland, who led the new work. “We leapt on it, and studied it in every way we could think of — but never managed to find any obvious sign that lack of the prion was causing it harm.”

In fact, at first glance, lack of prions seemed like a good thing because it made mice immune to prion infection.

But four years ago, Aguzzi started to think again about a generally overlooked 1999 paper² by researchers in Japan that suggested the lack of prion protein caused the degeneration and demyelination of nerves outside the brain. He decided to undertake a thorough and systematic analysis of prions’ effects on such peripheral nerves.

Together with his colleagues, he studied four different strains of mice lacking the gene for the prion PrP^C. In every mouse they tested, regardless of strain, they found early evidence of myelin damage just six weeks after birth. By the age of two months, the nerves were extensively demyelinated, and the mice had become more sensitive to pain.

“Because there is no myelin damage at birth, we assumed prions are needed to maintain the quality of the myelin sheath, which diminishes throughout life,” says Aguzzi. Accordingly, when the researchers re-introduced prion proteins specifically into nerves, the demyelination did not occur. Curiously, however, only variants of prion proteins susceptible to cleavage by enzymes were effective.

But no variant of prion protein was able to prevent demyelination when introduced specifically into the Schwann cells that surround and support peripheral nerve cells. “This surprised us,” says Aguzzi, “since Schwann cells actually do the job of manufacturing fresh myelin.”

Aguzzi concludes that when nerves’ sheathes are suffering wear and tear, the nerves enzymatically cleave their prion proteins, releasing fragments that travel to Schwann cells, where they signal activation of myelin repair.

Brain effects

He also has a hunch, supported by preliminary data, that prion proteins will turn out to play the same part in supporting myelination in the brain. “So it is going to be interesting to see if prions play any role in demyelinating diseases that stem from the brain,” he says.

“Treatment of CJD targets prion proteins, which are assumed to be doing the damage,” says Mead. “But if CJD did indeed turn out to be caused by absence of prions, then we would have to rethink this therapeutic approach.”

Claude Carnaud, an immunologist working on prions at the INSERM research unit of the Pierre and Marie Curie University – Paris 6, says that some brain disorders that have been considered inflammatory in origin look like they may instead involve an absence of prions in the brain, at least in mice. “It will be very interesting to see if this also applies to multiple sclerosis,” he says. 

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  References

  
  
  
  
  1. Bremer, J. et al. Nature Neurosci. doi:10.1038/nn.2483 (2010).
     
  2. Nishida, N. et al. Lab. Invest. 79, 689-697 (1999).

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Prions ‘may keep nerves healthy’

Removing prion proteins led to a breakdown of the myelin sheath surrounding the nerve 출처 : BBC 00:02 GMT, Monday, 25 January 2010 http://news.bbc.co.uk/2/hi/health/8476093.stm Experiments on mice may help scientists understand the workings of the prion protein linked to brain disease vCJD. Swiss researchers say there is evidence that prions play a vital role in the maintenance of the sheath surrounding our nerves. They say it is possible that an absence of prions causes diseases of the peripheral nervous system. One expert said there was growing evidence that the prion had a number of important roles in the body. As well as the latest research in the journal Nature Neuroscience, other studies have indicated prions may protect us from Alzheimer’s disease or even play a role in our sense of smell. Most people started by focusing on prions in relation to a human disease, and have only recently started to examine what it normally does Professor Nigel Hooper, Leeds University The prion protein only came to the attention of scientists in recent years as they searched for the cause of vCJD – the human variant of BSE, or Mad Cow Disease. This degenerative and incurable brain condition is now thought to be caused by a “mis-folded” version of the prion. However, there is still little understanding of what the protein is supposed to do in its normal, healthy, form. Healthy prions The study, by scientists at the University Hospital in Zurich, looked at mice bred with fewer prion proteins. While these mice are known to be resistant to prion diseases equivalent to vCJD in humans, they showed a number of abnormalities, including a degeneration, later in life, of the peripheral nerve cells, and the protective myelin sheath which surrounds them. Peripheral nerves are those which link the limbs and organs to the central nervous system – the spinal cord and brain. Looking more closely, researchers examined the effects of removing the prion protein in both the nerve cells themselves, and the Schwann cells surrounding them, which are responsible for making the myelin sheath. While removing protein from the Schwann cells had no effect, taking it from the neurons led to a breakdown of the myelin and degeneration of the nerve cells. They said that the knowledge that prion protein played some role in the healthy upkeep of nerve cells could offer a new avenue of research into diseases affecting humans. However, scientists caution that it is too early to pick out a particular peripheral nerve condition which might correspond to the mouse experiments. Recent work Professor Nigel Hooper, from the University of Leeds, agreed that the role of the protein was not well understood. His own work, published in 2007, suggested that it might offer some protection from the development of Alzheimer’s disease. But he said this was unlikely to be the complete answer. He said: “Most people started by focusing on prions in relation to a human disease, and have only recently started to examine what it normally does. “There is some evidence that it could have a number of different roles, depending on its whereabouts in the body – a recent paper linked it to olfaction or the sense of smell.”

Manipulating brain inflammation may help clear brain of amyloid plaques

출처 : http://www.physorg.com/news175430394.html

In a surprising reversal of long-standing scientific belief, researchers at the Mayo Clinic campus in Florida have discovered that inflammation in the brain is not the trigger that leads to buildup of amyloid deposits and development of Alzheimer’s disease.

In fact, inflammation helps clear the brain of these noxious amyloid plaques early in the disease development, as seen from studies in mice that are predisposed to the disorder, say the researchers in the online issue of the FASEB Journal.

“This is the opposite of what most people who study Alzheimer’s disease, including our research group, believed,” says the study’s lead investigator Pritam Das, Ph.D., an assistant professor in the Department of Neuroscience. “And it also suggests that we can take advantage of the brain’s own immune cells by directing them to remove amyloid plaques from the brain, thus protecting the brain against their harmful effects.”

The study tested the widely held belief that inflammation in the brain increases the production and buildup of a toxic protein known as amyloid beta (Aβ). Clumps of this protein in the brain are the hallmark pathological feature of Alzheimer’s disease.

“The belief was that when the brain’s immune cells, microglia, are activated following the initial buildup of amyloid plaques, the inflammation that ensues stimulates the brain cell’s machinery to produce more Aβ, which then leads to more inflammation,” Dr. Das says. “This chronic activation of immune cells results in a self-reinforcing feedback loop that promotes more and more Aβ deposition and inflammation, eventually leading to malfunction and death of brain neurons.”

Although this notion, which came mostly from studies in laboratory cells, was accepted throughout the scientific community, the Mayo Clinic researchers developed a way to test it in a living organism — and they expected to see the same result.

“We had initiated these studies using our new in vivo model to confirm whether inducing inflammation in the brain would in fact exacerbate the disease,” Dr. Das says.

The researchers used a technique known as “Somatic Brain Transgenesis” to increase expression of Interleukin-6 (IL-6), a cytokine that stimulates an inflammatory immune response in the brains of young mice predisposed to developing age-progressive amyloid plaques. This powerful technology allows researchers to express any gene of interest in specific parts of the body by tagging the gene onto Adeno-associated viruses, which are inert. In this way, they can study the function of any protein in the brain, and also test its potential therapeutic use.

They found that IL-6 triggered inflammation throughout the brain, and they expected to see a big buildup of plaque as well as damage to brain neurons. “Instead, to our surprise, we found that the inflammation prevented plaques from forming and cleared whatever plaque that was already there,” Dr. Das says.

Given this unexpected result, they performed additional experiments using different strategies. “First, we expressed IL-6 in the brains of newly born mice that are yet to develop any amyloid plaques and, secondly, we expressed IL-6 in the brains of mice with pre-existing plaque pathology,” he says. “In both these cases, we got similar results — the presence of IL-6 leads to the clearance of amyloid plaques from the brain.”

The researchers then performed experiments to determine how the amyloid plaques were removed from the brain. Their analysis revealed that the inflammation induced by IL-6 in the brain directed the microglia cells to remove the amyloid plaques from the brain. Microglial cells do this by phagocytosis. “They gobble up the plaque, which they ‘see’ as a foreign invader, and break it apart,” Dr. Das says. Researchers also found that activated microglia cells were closely attached to the plaques and expressed proteins that help in removing the amyloid plaques from the brain.

Dr. Das hypothesizes that inflammation helps clear plaque early in the development of Alzheimer’s disease, but that at some point, continued production of the amyloid clumps in the brain overwhelms the ability of microglial cells to do their job. At that point, inflammation, chronically activated by presence of the amyloid plaque, can produce its own unhealthy effects on brain function.

“Indeed, it may be feasible to transiently and selectively manipulate the microglia cells to alter amyloid plaques in a manner that is both effective and tolerable,” he says. “However, given that chronic inflammation over years of insult may be detrimental, any intervention based on activation of the brain’s immune system must clearly strike a balance between the neuroprotective and neurotoxic effects,” cautions Dr. Das. “We need to study this phenomenon more thoroughly, but if we are right, it could have implications not only for Alzheimer’s disease but also other neurodegenerative disorders characterized by protein buildup in the brain, such as Parkinson’s disease.”

Source: Mayo Clinic (news : web)

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뇌 염증이 아밀로이드 플라그를 제거한다?

KISTI 『글로벌동향브리핑(GTB)』 2009-10-25

출처 : http://radar.ndsl.kr/tre_View.do?ct=TREND&clcd=M&clk=&lp=TM&gotoPage=5&cn=GTB2009100381

메이오 클리닉 플로리다 캠퍼스의 연구자들이 뇌의 염증이 아밀로이드(amyloid) 축적과 알츠하이머의 발병으로 이어지는 시발자가 아니며, 오히려 질병 발생 초기에 유해한 뇌의 아밀로이드 플라그를 제거하는데 도움이 될 수 있다는 것을 동물 모델에서 증명한 연구 결과를 “FASEB journal”에 보고하였다.

뇌에서 아밀로이드 단백질 덩어리는 알츠하이머 질환의 병리학적 특징이다. 뇌의 면역 세포인 미소교세포가 아밀로이드 플라그의 초기 축적 후에 활성화되면, 염증은 뇌세포가 더 많은 아밀로이드 베타를 생산하도록 자극하고 그것은 더 많은 염증으로 이어진다고 믿어져왔다. (GTB2009070303, GTB2007090242) 만성적 면역 세포의 활성은 자가-강화 피드백 고리를 야기하여, 아밀로이드 베타 침적과 염증을 더욱 더 자극하고 결국 뇌 신경의 기능 장애와 사멸로 이어진다. 실험실 세포에서의 연구들로부터 이루어진 이 개념이 수용되고 있고, 메이오 연구팀 또한 살아있는 유기체에서 그것을 시험하며 같은 결과를 예상했었다. 그들은 새로운 동물 모델을 잉요해 뇌의 염증이 독성 단백질인 아밀로이드 베타의 생성과 축적을 증가시켜 질병을 가속화시키는지를 확인하고자 했다.

연구팀은 알츠하이머 환자에서 병리적 상호작용에 의해 증가되어 있는 전-염증성 사이토카인인 인터루킨-6(interleukin-6)가 생체 내에서 아밀로이드 베타의 침적과 아밀로이드-베타 전구 단백질 (A precursor protein, APP)의 가공에 대한 영향을 시험하기 위해 APP 유전체변환(transgenic) 쥐인 TgCRND8과 TG2576를 만들어 쥐의 뇌에 IL-6를 과발현시켰다.

그들은 IL-6가 강력한 미소교세포증(gliosis)를 야기하며 뇌 전체에 염증을 개시한다는 것을 알았고, 뇌 신경에 커다란 플라그의 축적을 기대했다. 그러나 놀랍게도 염증은 플라그의 존재 여부와 상관 없이 플라그의 형성을 막거나 제거한다는 것을 알았다. Il-6의 과발현은 TgCRND8 쥐의 뇌에서 아밀로이드 베타의 침적을 약화시킨다. 예상치 못한 결과로 부가적인 실험이 수행되었다. 아밀로이드 플라그가 아직 발생하지 않은 새로 태어나는 쥐의 뇌와 이미 플라그가 존재하는 쥐의 뇌에서 IL-6를 발현시켰다. 두 가지 경우 모두 IL-6의 존재가 뇌에서 아밀로이드 플라그의 제거로 이어진다는 것을 보였다. 연구팀은 어떻게 아밀로이드 플라그가 뇌에서 제거되는지를 시험하였다. 연구팀은 실험은 뇌에서 IL-6에 의해 유도된 염증이 뇌로부터 아밀로이드 플라그를 제거하기 위해 소교세포에게 직접 지시한다는 것을 알았다. 소교세포는 식세포 활동을 통해 플라그를 삼키는데, 플라그는 외부 침입물질로 인식되기 때문이다. 그들은 또한 활성화된 소교세포가 플라그에 밀착하여 뇌로부터 아밀로이드 플라그를 제거하는 데 도움이 되는 단백질을 발현한다는 것을 알았다. IL-6에 유도된 뇌염증은 TgCRND8에서 APP 가공에서 아무런 작용을 하지 않았고, 어린 Tg2576 쥐에서는 APP 가공이나 아밀로이드 베타의 정상 수준에 어떤 영향도 없었다.

이런 결과는 IL-6에 의해 매개된 소교세포증이 아밀로이드 병리를 가속화하는 신경독성적피드백 고리를 매개하기 보다는 잠재적으로 아밀로이드 베타 플라그 제거의 강화로 인해 질병 초기에 이롭다는 것을 제안한다. 연구팀은 염증이 알츠하이머 질환 발생 초기에 플라그를 제거하지만, 어떤 시점에서 뇌의 지속적인 아밀로이드 덩어리의 생산이 소교세포의 작용을 압도하게 된다고 가설을 세웠다. 그 시점에서 염증은 아밀로이드의 존재에 만성적으로 활성화되어, 뇌 기능에 해로운 작용을 산출할 수 있다는 것이다.