They discover the mechanism of progression of Alzheimer’s in the brain

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They reveal that the processes that lead to Alzheimer’s disease develop in a very different way than previously thought, since its progression does not begin in a single point in the brain, but in multiple regions.

A team of scientists led by the University of Cambridge has discovered that the way in which Alzheimer’s disease develops is very different from what was previously believed. According to their research, which has been published in Science Advances, this pathology does not begin in a single point of the brain from which a chain reaction is generated that causes the death of brain cells, but rather it appears early in several areas of the brain , and the speed at which it kills the cells present in them, through the production of toxic proteins, is what limits the speed with which the disease progresses.

The study authors used postmortem brain samples from Alzheimer’s patients and positron emission tomography (PET) images from living patients ranging from mild cognitive impairment to diagnosed Alzheimer’s to assess aggregation of the protein tau, one of the the two key proteins involved in the disease.

Tau and beta-amyloid proteins accumulate in tangles and plaques, known as aggregates, causing brain cell death and shrinking of the brain, resulting in memory loss, personality and difficulties in carrying out daily tasks, symptoms that characterize Alzheimer’s, a type of dementia that affects around 44 million people in the world.

Prevent replication of aggregates to curb Alzheimer’s

The processes that take place inside the brain and lead to Alzheimer’s have been defined for many years by terms like “cascade” and “chain reaction.” This disease is difficult to study, as it develops over decades and the definitive diagnosis can only be made after examining samples of brain tissue from the patient once they have died.

Studies of the disease have been based largely on animal models, and results in mice suggested that it spreads rapidly because clumps of toxic proteins invade different parts of the brain. The new research, however, has used human data for the first time to analyze the processes that control the development of Alzheimer’s disease over time.

“When Alzheimer’s disease begins there are already aggregates in multiple brain regions, so trying to stop the spread between regions will do little to slow down the disease.”

The researchers combined five different sets of data and applied them to the same mathematical model; In this way, they observed that the mechanism that controls the rate of Alzheimer’s progression is the replication of aggregates in individual areas of the brain, and not the propagation of aggregates from one area to another.

“Alzheimer’s has been thought to develop in a similar way to many cancers: aggregates form in one region and then spread throughout the brain,” said Dr Georg Meisl, from Cambridge’s Yusuf Hamied Department of Chemistry and first author of the article. “But instead, we found that when Alzheimer’s disease begins there are already aggregates in multiple brain regions, so trying to stop the spread between regions will do little to slow down the disease.”

“This research shows the value of working with human data rather than imperfect animal models,” said Professor Tuomas Knowles, also from the Department of Chemistry and co-lead author. “It is exciting to see progress in this field; fifteen years ago we and others determined the basic molecular mechanisms for simple systems in a test tube; but now we can study this process at the molecular level in real patients, which is an important step towards one day developing treatments.”

The findings revealed that replication of tau aggregates is significantly slow, taking up to five years. “Neurons are surprisingly good at stopping the formation of aggregates, but we need to find ways to improve them further if we are to develop an effective treatment,” said co-lead author Professor Sir David Klenerman, from the UK Dementia Research Institute. at Cambridge University. “It’s fascinating how biology has evolved to stop protein aggregation.”

As the authors of the work have indicated, their methodology could be used to contribute to the development of treatments for Alzheimer’s by focusing on the key processes that occur when people develop the disease. In addition, the methodology could be applied to other neurodegenerative diseases, such as Parkinson’s. “The key discovery is that stopping aggregates from replicating rather than spreading will be more effective in the stages of disease that we study,” Knowles concludes.

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