January 16, 2022

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AD: First time to use Human brain samples to discover the replication of toxic proteins

AD: First time to use Human brain samples to discover the replication of toxic proteins



 

AD: First time to use Human brain samples to discover the replication of toxic proteins. 

The University of Cambridge used human brain samples for the first time to discover a way to replicate toxic proteins!

“Who can tell me who am I?” The protagonist played by Anthony Hopkins asked the ultimate question in the movie “Father Trapped in Time”.

 

The latest data released by the World Health Organization show that more than 55 million people worldwide suffer from dementia, and the number of patients is increasing at a rate of nearly 10 million new cases every year, which is equivalent to 1 person getting sick every 3 seconds.

It is estimated that by 2050, the number of people with dementia worldwide will reach 139 million. Most of this growth will occur in fast-growing and densely populated regions such as China, India, and Latin America.

 

This is a disease that is difficult to study because it has developed for decades, and a definite diagnosis can only be given after examining brain tissue samples after death.

 

Currently, researchers mainly rely on animal models to study this disease. However, animal models cannot reproduce the aggregation rate of two key proteins, tau protein and amyloid, which makes research progress very slow .

 

It has always been thought that Alzheimer’s disease develops in a similar way to many cancers: the toxic proteins that cause Alzheimer’s disease form aggregates in one area and then spread to the entire brain.

 

However, recently an international team led by the University of Cambridge broke this understanding: Alzheimer’s disease does not start from a single point in the brain and triggers a chain reaction leading to the death of brain cells, but exists in the brain early.

Different regions, and continue to replicate and expand over time . The rate at which the disease “kills” the cells in these areas by producing toxic protein clusters limits the overall progression of the disease.

 

AD: First time to use Human brain samples to discover the replication of toxic proteins. 

(Image source: Science Advances)

 

In Alzheimer’s disease, tau protein and β-amyloid (Aβ) form tangles and plaques (collectively called aggregates), causing brain cell death and brain atrophy.

This can lead to memory loss, personality changes, and difficulty in daily activities.

 

In this study, the research team used human samples-brain samples after death from Alzheimer’s disease patients, as well as live patients (from mild cognitive impairment patients to comprehensive Alzheimer’s disease patients). PET scan to track the accumulation of tau protein.

 

The researchers used five different tau quantification methods and applied them to the same mathematical model.

They observed that the mechanism that controls the progression of Alzheimer’s disease is the duplication of aggregates in various regions of the brain, rather than the aggregation of aggregates from one. Diffusion from one area to another .

 

AD: First time to use Human brain samples to discover the replication of toxic proteins. 

Illustrate the key process of tau aggregate formation

(A) Diffusion, representing the spatial relocation of existing aggregates

(B) Copy, that is, localize the production of new seeds from existing seeds

 

Based on the anatomical analysis of the brain of the deceased Alzheimer’s disease patient, the neurofibrillary tangles composed of Tau protein are divided into six stages of development, namely the Braak stage. From stage 1 to stage 6, neurofibrillary tangles in the brain gradually increase.

 

The research team observed that after Braak Phase 3, the distribution of tau protein changed rapidly over time.

At the same time, the reduction in replication significantly slowed the overall accumulation of tau. This means that after Braak Phase 3, the overall rate of tau protein accumulation is determined by the replication rate, and inhibition of replication will slow down the entire process to the greatest extent .

 

AD: First time to use Human brain samples to discover the replication of toxic proteins. 

Variation of seed concentration in different Braak stages

(A) Decreased diffusion rate

(B) Copy rate decreased

 

Interestingly, the replication speed of tau protein aggregates is very slow, requiring up to 5 years.

 

“Neurons are surprisingly good at preventing the formation of toxic protein polymers, but if we are to develop an effective treatment, we need to find ways to make them better.

How biology has evolved to prevent protein aggregation , It’s very attractive.” Professor David Klenerman of the British Dementia Institute at the University of Cambridge said, “The key finding is that it is more effective to prevent the replication of toxic protein aggregates rather than their spread during the stage of the disease we are studying.”

 

This research “refreshes” people’s understanding of the development of Alzheimer’s disease, and makes Alzheimer’s disease treatment a new journey.

 

But so far, there is still a lack of effective treatment drugs. People from all walks of life are following each other, constantly introducing new treatment methods.

 

A recent study published in Science Signaling, a sub-issue of “Science”, shows that the combination of two “old drugs” that have been on the market for decades not only significantly reduces the beta amyloid protein associated with Alzheimer’s disease in animal models.

Deposition, but also improves the animal’s memory and cognitive abilities . This provides another scientific basis for the treatment of Alzheimer’s disease.

 

AD: First time to use Human brain samples to discover the replication of toxic proteins. 

(Image source: Science Signaling)

 

In this study, researchers at Rush University Medical Center in the United States used a lipid-lowering drug gemfibrozil and vitamin A derivative retinoic acid for combined treatment.

They found that the combination of gemfibrozil and retinoic acid may change the role of astrocytes, making them a tool to help clear beta amyloid .

 

At the same time, in the mouse model of Alzheimer’s disease, the administration of these two drugs to the mice can significantly reduce the β-amyloid deposits in the mouse brain, and the cognitive function of the mice is two months after taking the drug. , And also improved compared with the control group .

 

So how do these two drugs work?

 

Further research found that gemfibrozil and retinoic acid can activate a receptor protein called PPARα in cells.

The high expression of the gene regulated by this protein, TFEB, can promote the degradation of β amyloid.

 

In addition, these two drugs also stimulate the expression of low-density lipoprotein receptor (LDLR), which plays a key role in mediating the uptake of beta amyloid by cells.

 

The combination of these two effects enhances the ability of astrocytes to uptake and degrade β-amyloid.

 

This combination therapy significantly reduces the deposition of beta amyloid in the brains of mice (red and green spots)

(Image source: reference)

 

Although this combination of “old medicine and new use” has been effective in mouse models, whether it can play the same role in humans requires further clinical verification in the future.

One advantage of exploring the new use of “old drugs” that have been on the market is that the safety of these drugs has been extensively verified, so clinical trials can be launched more quickly to test their efficacy.

It is reported that the project researchers have authorized the combination of gemfibrozil and retinoic acid to a company, and it is preparing to submit an IND application to test the effectiveness of this combination in clinical trials.

 

Currently, dementias such as Alzheimer’s disease are still incurable. With more and more research on the cause, it is hoped that over time, scientists can find a cure for Alzheimer’s disease and benefit patients.

 

 

References:

Aβ Clearance The Uptapped Potential of Astrocytes ? Retrieved November3, 2021,

AD: First time to use Human brain samples to discover the replication of toxic proteins. 

(source:internet, reference only)


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