One study reveals that Alzheimer's disease is a "dual prion disorder"

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Two proteins essential to the pathology of Alzheimer's disease act as prions, malformed proteins that spread through tissues as an infection by forcing normal proteins to adopt the same misfolded form, according to a new study conducted by UC San Francisco.

Using new laboratory tests, researchers were able to detect and measure specific and self-propagating prion forms of beta-amyloid (A-β) and tau proteins in the postmortem brain tissue of 75 patients with Alzheimer's disease. In a striking finding, higher concentrations of these prions in human brain samples were strongly associated with early forms of the disease and at the younger age of death.

Alzheimer's disease is currently defined according to the presence of toxic aggregations of proteins in the brain, called amyloid plaques and tau tangles, accompanied by cognitive decline and dementia. . But attempts to treat the disease by removing these inert proteins have been unsuccessful. New evidence that active A-β and tau prions may be at the root of the disease – published May 1, 2019 Translational medicine science– could lead researchers to explore new therapies that focus directly on prions.

"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 Dr. Stanley Prusiner. lead author and director of the UCSF's Institute of Neurodegenerative Diseases, which is part of the UCSF Weill Neuroscience Institute. "The fact that prion levels also seem to be related to the longevity of patients should change our vision of the path to follow for developing treatments for the disease." We need a radical shift in disease research. Alzheimer's, and that's what this article does.This document could catalyze a major shift in research on AD. "

What are prions?

The prions are misfolded versions of a protein that can spread as an infection by forcing normal copies of this protein into the same self-propagated and misfolded form. The original prion protein, PrP, was identified by Prusiner in the 1980s as the cause of Creutzfeldt Jakob disease (CJD) and bovine spongiform encephalopathy, also known as the name of mad cow disease, which was spread by the consumption of meat meal and bone tinged with PrP prions. It was the first time that a disease infected people not by an infestation of an organism such as a bacterium or a virus, but through an infectious protein. Prusiner was awarded a Nobel Prize for this discovery in 1997.

Prusiner and his colleagues have long suspected that PrP is not the only protein capable of acting as a self-propagating prion, and that different types of prions could be responsible for other neurodegenerative diseases caused by the disease. progressive toxic accumulation of misfolded proteins. For example, Alzheimer's disease is defined by plaques of A-β and tau tangles that progressively propagate destruction in the brain. Over the last decade, laboratory studies at UCSF and elsewhere have begun to show that amyloid plaques and tau tangles from diseased brains can infect healthy brain tissue in the same way as PrP, but much more slowly.

data-src = "https://3c1703fe8d.site.internapcdn.net/" newman / gfx / news / hires / 2019 / 5cc965bdc37d9.jpg "data-sub-html =" The new cell tests of scientists could evaluate the presence of beta-amyloid (top row), alpha-synuclein (middle row), or tau proteins (bottom row) in human kidney cells, as indicated by bright orange dots Credit: A. Aoyagi et al. Translational medicine science (2019) ">

Many scientists have been reluctant to accept that A-β and tau are self-producing prions – rather calling them "prion-like" – because, unlike PrP prions, they were considered infectious only by highly controlled laboratory studies. However, recent reports have documented rare cases of patients treated with growth hormone from human brain tissue, or who have received a protective dura mater transplantation of the brain, who have developed plaques. A-β at middle age long before they appear in cells. anyone without a genetic disorder. Prusiner argues that these results argue that Aß and tau are prions, although they spread more slowly than the very aggressive PRP prions.

In response to these debates, Prusiner used to quote a speech made in 1969 by neuroscientist Bernard Katz: "There is one type of scientist who, if he had the choice, would prefer to use the toothbrush. from his colleague to his terminology! "

Laboratory bioassays reveal Aß and Tau prions in human post-mortem brain samples

In the new study, researchers combined two newly developed laboratory tests to rapidly measure the presence of prions in human tissue samples: a new A-β detection system developed in the Prusiner lab and a tau prion test previously developed by Marc Diamond, Ph.D., a former UCSF faculty member who is now director of the Center for the Treatment of Alzheimer's Disease and Neurodegenerative Disease at the UT Southwestern Medical Center.

In contrast to previous animal models that took months to reveal the slow spread of A-β and / or tau prions, these cellular tests measure infectious prion levels in just three days, allowing researchers to efficiently quantify levels for the first time. of tau and A-β prions in processed extracts of post-mortem brain samples. In the new study, they applied the technique to autopsied brain tissue from more than 100 people who died of Alzheimer's disease and other forms of neurodegeneration, which were collected in US depots, in Europe and Australia.

In trials comparing samples of patients with Alzheimer's disease to those who died from other diseases, prion activity corresponded exactly to the distinct protein pathology established in each disease: in 75 brains of Alzheimer's disease, the activity of prions A-β and tau was high; in 11 samples of patients with cerebral amyloid angiopathy (AAC), only A-β prions were observed; and in 10 tau-related tau-type frontalotemporal lobar degeneration (FTLD) samples, only tau prions were detected. Another recently developed biological assay for alpha-synuclein prions revealed that these infectious particles in seven samples from patients with multisystemic atrophy (MSA) -dependent degenerative disorders to synuclein.

"These tests are changing the game," said co-author and protein chemist William DeGrado, Ph.D., professor of pharmaceutical chemistry and a member of the UCSF Cardiovascular Research Institute, who helped design and develop the analysis of the present study. . "Previously, Alzheimer's research focused on collateral damage in the form of deadly misfolded proteins, which form plaques and tangles, and it turns out now that it is the activity of the prions that is in correlation with the disease, rather than the amount of plaque and tangles at the time So, if we want to succeed in developing effective therapies and diagnoses, we need to target active prion forms, rather than the large amount of protein in the plates and entanglements. "

Activity of A-β and Tau Prions Related to the Longevity of Alzheimer Patients

The most remarkable finding of this new study is perhaps the discovery that the self-propagating prion forms of tau and β-β are the most infectious in the brain of Alzheimer's patients who die to a young person. age of genetic forms of the disease, but much less prevalent in patients who died at a later age.

In particular, compared to measurements of the overall accumulation of tau – which is known to increase with age in the brain of Alzheimer's – the researchers found a remarkable exponential decline in abundance relative prion forms of tau with age. When the researchers plotted their data, they found a very strong correlation between tau prions and age at death of patients: relative to the general level of tau, the amount of tau prions in the brain of a patient who died at age 40 was on average 32 times higher. higher than in a patient who died at age 90.

"I still remember where I was sitting and from the time I saw these data a year ago," said co-author and researcher Lead in Neurodegeneration, William Seeley, MD, Professor of Neurology at UCSF Memory and Aging. Center that runs the UCSF Neurodegenerative Disease Brain Bank, which provides the tissue used in the study. "I have very rarely, if ever, seen this kind of correlation in human biological data." Now the job is to find out what correlation means. "

The research raises a number of questions that will need to be addressed in future studies, including whether differences in prion infectivity could explain the long-standing mystery that explains why Alzheimer's disease progresses at similar speeds. different in different patients. Other outstanding research questions include whether higher prion levels in brain samples from younger patients are related to the early onset of the disease or how quickly it progresses, and whether lower prion levels in older brains reflect less "infectious" prion variants or rather some brain capacity of these patients to get rid of misfolded proteins.

Evidence that prion forms of A-β and tau play a specific role in Alzheimer's disease – a phenomenon that can not be captured simply by counting amyloid plaques and tau tangles in patients' brains – also raises questions about current approaches to Alzheimer's diagnosis, and drug discovery, say the authors, who hope their new tests will spur renewed interest in developing therapies targeting Prion proteins, now measurable.

"We have recently seen many seemingly promising treatments against Alzheimer's disease fail in clinical trials, which has led some to think that we are targeting the wrong proteins," said Carlo Condello, Ph.D. One of the main authors of the study. "But what would happen if we had not just designed drugs against the distinctive prion forms of those proteins that actually cause the disease? Now that we can effectively measure the prion forms of A-β and We hope that we can develop drugs that: prevent them from forming or spreading, or help the brain to eliminate them before they cause damage. "