They discover the key to the progression of Alzheimer’s in the brain

Knowing how Alzheimer’s progresses is one of the great aspirations of the neuroscientists who investigate this neurodegenerative disease that affects some 44 million people all over the world. This evil occurs when two types of proteins (tau and beta-amyloid) they accumulate in small plaques or aggregates that cause brain cell death and associated damage. But, How fast are these changes taking place and what is the key moment?

Until now scientists focused mainly on propagation: spread of these toxic proteins in the early stages of Alzheimer disease from the hippocampal regions to other tissues was the main focus of interest. One of the most widespread hypotheses, in fact, is that This progression occurs in two stages or “strokes”: a first phase in which tau proteins spread through various regions until reaching the stage called “Vomit III“, In which beta-amyloids also begin to accumulate and the development of the disease accelerates.

Now, a new work published by the team of David Klenerman from the University of Cambridge points out that the disease develops in a very different way than previously thought and their results, they assure, open new paths for possible treatments.

It’s not the trip, it’s the explosion

In the work published this Friday in Science Advances magazine, researchers have developed a mathematical model from five different data sets from studies in human and animal brains on parameters related to disease progression. And when applied to this very simple first model, the researchers have observed that the mechanism that controls the rate of progression in Alzheimer’s disease it is the replication of aggregates of tau proteins in individual regions of the brain, and not the spread of aggregates from one region to another, as believed.

“When Alzheimer’s disease begins, there are already aggregates in multiple regions of the brain”

“It was thought that Alzheimer’s developed in a manner similar to many cancers: the aggregates are formed in a region and then spread throughout the brain ”, he says Georg Meisl, main author of the article. But instead we found that when Alzheimer’s disease begins there are already aggregates in multiple regions of the brainSo trying to stop the spread between regions will do little to stop the disease. “

The importance of “seeds”

For the Spanish pathologist Alberto Rábano, who has been investigating the evolution of Alzheimer’s for years at the command of the CIEN Foundation Tissue Bank, it is a leading and revealing study on the development of the disease. “They have gathered strategic data with different methodologies, animal models, human tissue lesion counts, or molecular imaging with PET-Tau, around a simple mathematical model ”, he explains to Vozpópuli.

The model compared the spread with the replication of toxic proteins over time | Georg Meisl et al. Science Advances

According to its authors, this is the first time that human data has been used to track which processes control the development of Alzheimer’s disease over time, something that has been made possible in part thanks to advances in PET scanning and improvements in the sensitivity of other techniques.

“We have been thinking in terms of propagation and that is useless”

“The novelty is that the result fits very well with the data we have on patients and those that we observe in PET-Tau ”, Rábano summarizes,“ and the authors send a main message: that we have always been thinking in terms of propagation and that is useless, because the limiting factor of the model is the amount of tau added, the pathological burden which is what is doing toxic damage to cells ”.

In other words, what they have discovered is that it is not so decisive that the toxic proteins have reached certain areas of the brain, as it would happen in a tumor, but that once in each place they are able to grow exponentially, like small “seeds” that condition the progress of the disease. “Specifically,” write the authors, “we found that a lower rate of seed replication always slows down overall progression, while a lower rate of spread only does so in certain circumstances ”.

The speed of Alzheimer’s

Among the results produced by the model, which coincide with the clinical observations, is that it takes about five years for tau proteins to spread to different places in the brain and symptoms begin to manifest. Until then, the disease does not show its face at any time, which makes any possible intervention difficult. Those five years are the time it takes for these “seeds” to germinate and begin the progress of the disease.

“Alzheimer’s would look more like a virus than cancer, but a virus that is mutating”

The model that is refuted with this evidence is the ‘cancer-like’ model, according to which there is a place where it begins and it all depends on where the metastases are being sent ”, explains Dr. Rábano. “What we see is that in Alzheimer’s this happens, but slowly, and the limiting factor is not the spread, in terms of rate, but the rate at which they are multiplying those proteins”. In that sense, he admits, “Alzheimer’s it would look more like a virus than a cancer, but to a virus that is mutating, because it is being replicated better and better ”.

According to Alberto Rábano, who has not participated in the study, the new discovery will help clinicians to better explain the high variability they see between patients, some of which have a rapid advance of the disease and others that can go up to thirty years without developing it. “So far we have not found the causes,” he says. “Maybe the engine of that difference is the ability of progression of the ‘seeds‘”. In fact, one of the possibilities that researchers are considering is that there is different strains of tau proteins capable of advancing at more or less speed, as with prions or viruses that spread faster from cell to cell.

“The research would be turned upside down if there were drugs in sight that were capable of stopping this replication”

What this new work indicates is that it is in this multiplication rate where the motor of the progression of the disease is and where they can be searched new therapeutic targets. In short, what the ability of toxic proteins to multiply is much more important than their ability to travel. “These proteins have traveled for a long time and once they reach any place in the brain, there is a quantum jump, they multiply faster,” says Rábano. “The investigation would be turned upside down if there were drugs in sight that were capable of stopping this replication”.

Reference: In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease (Science Advances) | DOI 10.1126/sciadv.abh1448


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