Scientists Identify Cause of Alzheimer’s Disease Progression in Brain – Much Different Than Previously Thought



For the first time, researchers have used human data to quantify the speed of different processes that lead to Alzheimer’s disease and found that it develops in a very different way than previously thought. Their findings could have important implications for the development of potential treatments.

The international team, led by the University of Cambridge, found that instead of starting from a single point in the brain and triggering a chain reaction that leads to the death of brain cells, Alzheimer’s disease reaches early on in different regions of the brain. The speed with which the disease kills cells in these areas, through the production of toxic protein clumps, limits the rate at which the disease progresses overall.

The researchers used postmortem brain samples from patients with Alzheimer’s disease, as well as CT scans from living patients, ranging from those with mild cognitive impairment to those with advanced Alzheimer’s disease. , to track aggregation of tau, one of the two key proteins. involved in the state.

“This research shows the value of working with human data instead of imperfect animal models.” – Tuomas knowles

In Alzheimer’s disease, the protein tau and another protein called beta-amyloid build up in tangles and plaques – collectively known as aggregates – causing brain cell death and brain shrinkage. This leads to memory loss, personality changes, and difficulty performing daily functions.

By combining five different data sets and applying them to the same mathematical model, the researchers observed that the mechanism controlling the rate of progression of Alzheimer’s disease is the replication of aggregates in individual regions of the brain, not the propagation of aggregates from one region to another.

The results, published in the journal Scientists progress, open new avenues for understanding the evolution of Alzheimer’s disease and other neurodegenerative diseases, and new avenues for developing future treatments.

For many years, the processes in the brain that lead to Alzheimer’s disease have been described using terms such as “cascade” and “chain reaction”. It is a difficult disease to study, as it develops over decades, and a definitive diagnosis can only be made after examining samples of brain tissue after death.

For years, researchers have relied heavily on animal models to study the disease. The results from the mice suggest that Alzheimer’s disease spreads quickly, as toxic protein clumps colonize different parts of the brain.

“The idea was that Alzheimer’s disease develops in a similar way to many cancers: aggregates form in one region and then spread to the brain,” said Dr Georg Meisl of the Yusuf chemistry department. Hamied of Cambridge, first author of the article. “But instead, we found that when Alzheimer’s disease starts, there are already aggregates in several areas of the brain, so trying to stop the spread between areas won’t do much to slow it down. disease.”

This is the first time that human data has been used to track the processes that control the development of Alzheimer’s disease over time. This was made possible in part by the chemical kinetics approach developed at Cambridge over the last decade that allows modeling of the processes of aggregation and propagation in the brain, as well as the progress of PET and improvement. the sensitivity of other brain measurements.

“This research shows the value of working with human data instead of imperfect animal models,” said co-lead author Professor Tuomas Knowles, also from the chemistry department. “It’s exciting to see the advancements in this area – fifteen years ago, basic molecular mechanisms were determined for simple systems in a test tube by us and others; but now we are able to study this process at the molecular level in real patients, which is an important step in one day developing treatments.

The researchers found that the replication of tau aggregates is surprisingly slow, taking up to five years. “Neurons are surprisingly good at preventing aggregate formation, but we have to find ways to make them even better if we are to develop an effective treatment,” said co-lead author Professor Sir David Klenerman from UK Dementia Research Institute. at the University of Cambridge. “It’s fascinating to see how biology has evolved to stop protein aggregation. “

The researchers say their methodology could be used to help develop treatments for Alzheimer’s disease, which affects an estimated 44 million people worldwide, by targeting the most important processes that occur when humans develop the disease. In addition, the methodology could be applied to other neurodegenerative diseases, such as Parkinson’s disease.

“The key finding is that stopping the replication of aggregates rather than spreading them will be more effective at the stages of the disease we have studied,” Knowles said.

The researchers now plan to examine the earlier processes of disease development and expand the studies to other diseases such as frontal temporal dementia, traumatic brain injury, and progressive supranuclear palsy where tau aggregates also form in the body. course of the disease.

Reference: “In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease” by Georg Meisl, Eric Hidari, Kieren Allinson, Timothy Rittman, Sarah L. DeVos, Justin S. Sanchez, Catherine K. Xu, Karen E. Duff, Keith A. Johnson, James B. Rowe, Bradley T. Hyman, Tuomas PJ Knowles and David Klenerman, October 29, 2021, Scientists progress.
DOI: 10.1126 / sciadv.abh1448

The study is a collaboration between researchers from the UK Dementia Research Institute, the University of Cambridge and Harvard Medical School. Funding is recognized by Sidney Sussex College Cambridge, European Research Council, Royal Society, JPB Foundation, Rainwater Foundation, NIH and NIHR Cambridge Biomedical Research Center which supports Cambridge Brain Bank.



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