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This week's researchers say their work should give new meaning to how Alzheimer's disease manifests itself. They argue that progression of Alzheimer's disease is caused by a very specific form of two proteins that play a crucial role in the disease, and that these forms must be considered as prions – potentially infectious proteins that replicate. of themselves by turning their brothers into a misfolded version of themselves. .
In simple terms, people with Alzheimer's disease have a brain that is filled with rigid and clustered deposits of beta and tau proteins, amyloid and amyloid plaques respectively. It has long been assumed that if we could prevent these deposits, particularly plaques, from spreading them or dissociating them, we could delay or even prevent Alzheimer's disease. But this theory has been devastating in recent years, because the trials of an anti-amyloid drug have not slowed the disease in humans.
The researchers behind this latest study, based mainly at the University of California at San Francisco (UCSF), say that it is not the final phases of beta-amyloid and tau that are problematic; it is the oldest and prion-like forms of both proteins that are the real culprits. The plates and entanglements in this theory are essentially the "dead", inactive remnants of amyloid prions and tau.
"You're stuck with these names and people really care about them. I do not know, maybe being a young generation, I'm more willing to give up a definition. "
Stanley B. Prusiner, neurologist and biochemist, is one of the researchers behind this new argument. His work, awarded by a Nobel Prize, established for the first time that prions are at the root of many rare but universally fatal brain disorders, such as Creutzfeldt-Jakob disease in humans and the scrapie. in sheep.
The prions that cause these diseases are actually the mutated and misfolded form of a protein naturally produced by many mammalian species, also called prion protein, or PrP. Although it does not have genetic material such as a virus or bacteria (and is even further from the concept of life), this mutant PrP is more autonomous than itself, forcing in a way or another normal PrP to fall back into the same configuration, thus destroying the brain along the process. way.
Scientists have also found proteins in fungi that resemble PrP, as they can also be transformed into different forms that replicate themselves, or even other prion-like proteins in slugs. sea and mammals. Unlike the poor PrP, these proteins do not seem to cause disease and could even play a beneficial role in the survival of their hosts (in humans, help us form long-term memories).
Other animal research has also shown that amyloid and tau can act and spread like conventional prions under certain conditions. And there is even evidence of people with Alzheimer's disease through medical procedures, although some people have contracted classical prion diseases from contaminated surgical equipment or transplants (to be clear, these incidents are extremely rare and no one claims that Alzheimer's disease is infectious in the same way the flu virus, it's just that it can behave like a classical prion disease).
Given all of the above, the team wants to expand the definition of prions to include amyloid, tau and other naturally occurring protein that can turn into a form that replicates itself. -even.
"It's a very generic definition that can encompass all these different disease-related proteins, capable of spreading via a prion mechanism, but most importantly, it also incorporates all those functional prions that we find in yeast and elsewhere. ", co-principal author, Carlo Condello. , assistant professor of neurology at the Institute of Neurodegenerative Diseases of the UCSF, told Gizmodo.
"I think it shows without a shadow of a doubt that the beta and tau proteins of amyloid are two prions and that Alzheimer's disease is a double prion disorder in which these two dishonest proteins destroy the brain "
Condello and his team also wish to rephrase the way scientists conceptualize Alzheimer's disease and other neurological disorders closely related to abnormal proteins, such as Parkinson's disease – to begin placing them under cover. from prion disease and from there to better understand the disorder and finally, finally develop effective treatments.
"It's interesting to think that there are a number of diseases to which a person's name is attached – Alzheimer's disease, Parkinson's disease – but these names do not make sense of the mechanism by which they are treated. -tend … you get stuck with these names and these people hang on to them, "said Condello." I do not know, being maybe a younger generation, I'm more willing to give up a definition . "
Using both their test and a previously developed test for tau protein prions, they studied the brain of nearly 100 deceased patients with Alzheimer's disease or similar dementias and compared them to healthy controls.
In these brains, they found clear evidence of the spread of amyloid and tau prions in the brain, much like conventional prions. Another obvious link has been observed between people with frontotemporal dementia – a disease associated only with tau and non-amyloid prions – and tau prions. To their surprise, they also found that amyloid and tau prion levels decreased with the age of the elderly. The over 80s had the lowest prion levels of all, while the opposite was true among the youngest people who died with a hereditary form of Alzheimer's disease passed on in families. With tau in particular, the total amount of tau in the brain increased with age, although tau prion levels decreased.
The significance of this latest discovery is unclear at the moment, say the authors. We know that our genetic makeup can make us more vulnerable to Alzheimer's disease, especially when it occurs in relatively young people. So, perhaps, said Condello, those who survived longer had genetics that allowed them to better break toxic prions into plaques and entanglements than those who died young. Or maybe, just as there are different strains of viruses or bacteria, there are different forms of amyloid prion and tau that can shape the evolution of the disease differently.
"This is just the tip of the iceberg, and we naturally want to extend this search to hundreds or even thousands of cases. And what's nice is that the tests we've developed are fast and high throughput, allowing us to process these samples pretty quickly, "said Condello.
Regardless of future research, the authors say that their results already suggest that relying on tests or treatments that only take into account the total levels of tau and amyloid in a person's brain risk of sending researchers on the wrong track.
"I think it shows without a shadow of a doubt that the beta and tau proteins of amyloid are two prions and that Alzheimer's disease is a double prion disorder in which these two dishonest proteins destroy the brain, "said Stanley Prusiner, now director of the UCSF's Institute of Neurodegenerative Diseases, in a statement. "The fact that prion levels also seem to be related to the longevity of patients should change the way we think about how to develop treatments for the disease. We need a radical change in research on Alzheimer's disease, and that's what this document does. This document could catalyze a major shift in Alzheimer's research. "
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