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New research has found that sweeping away the "garbage" in brain cells can improve the memory of mice and may even cure Alzheimer's disease.
Image source: Pixabay, Albert Einstein College of Medicine translated by Xu Chuchu, edited by Wei Xiao.
Researchers at the Albert Einstein College of Medicine in the United States have designed an experimental drug that can reverse the Alzheimer disease in mice.
The main symptoms of Alzheimer's disease.
The working principle of the drug is to restore the cell's cleansing mechanism and eliminate unwanted proteins through digestion and circulation.
The study was published online in the journal Cell on April 22, 2021.
Ana Maria Cuervo, co-director of the Institute for Aging Research and Professor of Developmental and Molecular Biology at the Albert Einstein School of Medicine, is the co-leader of the research.
She said: “In the past, The findings made by mice are not always applicable to humans, especially in the study of Alzheimer’s disease.
But our current study found that the decline in cell cleaning ability is one of the causes of Alzheimer’s disease.
This phenomenon is not only reflected in mice, but also in human patients.
This discovery is very encouraging to us, because it shows that the drug may be equally effective in humans.
" Cuervo discovered this type of drug in the 1990s .
The existence of cell cleansing process, which is called "chaperone-mediated autophagy" (chaperone-mediated autophagy, CMA), has published more than 200 papers on its role in health and disease.Ana Maria Cuervo Image source: Albert Einstein College of Medicine As people age, the efficiency of CMA gradually decreases, and the risk of unnecessary protein accumulating into insoluble masses that damage cells is also gradually increasing.
In fact, the presence of toxic protein polymers in the patient’s brain is a common feature of Alzheimer’s disease and all other neurodegenerative diseases.
The paper published in "Cell" reveals the dynamic interaction between CMA and Alzheimer's disease: the lack of CMA in neurons can cause Alzheimer's disease and vice versa.
The results of the study indicate that drugs that accelerate CMA may bring hope to the treatment of neurodegenerative diseases.
Establishing the link between CMA and Alzheimer's disease In this study, Cuervo's team first investigated whether damaged CMA can cause Alzheimer's disease.
To this end, they genetically modified a mouse to make the excitatory neurons in the brain lack CMA.
It turned out that the lack of CMA in only one type of brain cell is enough to cause short-term memory loss, walking impairment, and other problems often found in rodent models of Alzheimer's disease.
In addition, in the absence of CMA, protein homeostasis (proteostasis) will be severely disrupted, and this is the cell's ability to regulate the proteins it contains.
Under normal circumstances, soluble proteins become insoluble, with the risk of coagulation into toxic polymers.
Cuerve's reverse suspicion of this phenomenon is also correct: early Alzheimer's disease can also damage CMA.
She and her colleagues studied a mouse model equivalent to early Alzheimer's disease, in which the brain neurons of the mouse can produce defective copies of the tau protein.
There is evidence that this abnormal copy of the tau protein will clump together to form neurofibrillary tangles (neurofibrillary tangles), leading to Alzheimer's disease.
The hippocampus (hippocampus) is an area of the brain that is essential for memory and learning.
The research team focused on the CMA activity in neurons in this area and found that compared with the animals in the control group, the neurons in the diseased mice The CMA activity is significantly reduced.
What about human patients with early Alzheimer's disease? Does it also hinder CMA (of human cells)? In order to find the answer, the researchers performed single-cell RNA sequencing on the brain neurons of Alzheimer's disease patients after death, and compared them with a set of data from a control group of healthy individuals, hoping to understand the role of CMA in the brain tissue of patients.
Activity level.
Sure enough, patients in the early stage of Alzheimer's disease have a certain degree of inhibition of CMA activity; in the late stage of Alzheimer's disease, this inhibition is more serious.
Cuervo said: “When people reach the age of 70 or 80, CMA activity levels are usually reduced by about 30% compared to when they were younger.
Although most people’s brains can compensate for this decline, if neurodegenerative diseases are added at this time This may have a devastating effect on the normal protein composition of brain neurons.
Our research shows that CMA dysfunction and the pathological process of Alzheimer’s disease work synergistically, which will greatly accelerate the development of the disease.
"A kind of "cleaning" "New neuron drug based on this encouraging discovery, Cuervo and his team have developed a new drug that shows the potential to treat Alzheimer's disease.
Cuervo said: "We know that CMA can digest defective tau protein and other proteins.
But in Alzheimer's disease and other neurodegenerative diseases, a large number of defective proteins make CMA overwhelmed and eventually paralyzed.
And we Of drugs can revive the efficiency of CMA by increasing the level of key components of CMA.
"In CMA, a kind of protein called chaperones binds to damaged or defective proteins in the cells of the body, and transports them to the lysosomes of the cell as "cargo".
.
as an internal filled with membrane-bound enzyme organelles, lysosomes and digestion can play a role in waste recycling.
However, in order to successfully these "goods" into lysosomes, chaperones they must first be "docked "referred to LAMP2A receptor protein" docks "on the receptor and this film is long in the lysosomes.
more LAMP2A lysosomal receptors, CMA activity may be higher.
this is The new drug called CA works by increasing the number of LAMP2A receptors.
LAMP2A in neurons participates in autophagy.
Picture source: Courtesy of Albert Einstein College of Medicine The number of bodies is the same.
But these receptors degrade faster than age.
So in the elderly, there are often fewer available receptors to transport unwanted proteins to the lysosome.
CA is a drug that can restore the amount of LAMP2A to a youthful level, allowing CMA to effectively get rid of tau protein and other proteins, so that they will not form those toxic protein clumps.
Also in April, Dr.
Cuervo’s team reported in Nature Communications that they had isolated lysosomes from the brains of Alzheimer’s patients for the first time, and observed a significant increase in the number of LAMP2 receptors.
The reduction will result in the loss of human CMA, as found in animal models. Researchers tested CA in two different mouse models of Alzheimer's disease and found that after 4 to 6 months of oral medication, the memory, depression, and anxiety problems of these two diseased mice were improved and treated The latter mice were the same or almost the same as the healthy control mice.
Cuervo added: "The important thing is that the animals in these two models have shown symptoms of the disease.
Before the drug is administered, their neurons have been blocked by toxic proteins.
This means that the drug can even be Helps maintain neuron function in the later stages of the disease.
Another finding that excites us is that the drug also significantly reduces the phenomenon of gliosis, that is, inflammation and scars around neurons in the brain.
Glial hyperplasia and toxicity Protein is related, and it is currently known to play an important role in the persistence and deterioration of neurodegenerative diseases.
"Research shows that even if CA is taken for a long time and every day, this treatment does not seem to damage other organs.
The drug was designed by Dr.
Evripidis Gavathiotis, a professor of biochemistry and medicine, and co-leader of research.
It is reported that Cuervo and Gavathiotis have partnered with Life Biosciences of Boston, Mass.
to establish Selphagy Therapeutics.
The company is currently developing CA and related compounds for the treatment of Alzheimer's disease and other neurodegenerative diseases.
Image source: Pixabay, Albert Einstein College of Medicine translated by Xu Chuchu, edited by Wei Xiao.
Researchers at the Albert Einstein College of Medicine in the United States have designed an experimental drug that can reverse the Alzheimer disease in mice.
The main symptoms of Alzheimer's disease.
The working principle of the drug is to restore the cell's cleansing mechanism and eliminate unwanted proteins through digestion and circulation.
The study was published online in the journal Cell on April 22, 2021.
Ana Maria Cuervo, co-director of the Institute for Aging Research and Professor of Developmental and Molecular Biology at the Albert Einstein School of Medicine, is the co-leader of the research.
She said: “In the past, The findings made by mice are not always applicable to humans, especially in the study of Alzheimer’s disease.
But our current study found that the decline in cell cleaning ability is one of the causes of Alzheimer’s disease.
This phenomenon is not only reflected in mice, but also in human patients.
This discovery is very encouraging to us, because it shows that the drug may be equally effective in humans.
" Cuervo discovered this type of drug in the 1990s .
The existence of cell cleansing process, which is called "chaperone-mediated autophagy" (chaperone-mediated autophagy, CMA), has published more than 200 papers on its role in health and disease.Ana Maria Cuervo Image source: Albert Einstein College of Medicine As people age, the efficiency of CMA gradually decreases, and the risk of unnecessary protein accumulating into insoluble masses that damage cells is also gradually increasing.
In fact, the presence of toxic protein polymers in the patient’s brain is a common feature of Alzheimer’s disease and all other neurodegenerative diseases.
The paper published in "Cell" reveals the dynamic interaction between CMA and Alzheimer's disease: the lack of CMA in neurons can cause Alzheimer's disease and vice versa.
The results of the study indicate that drugs that accelerate CMA may bring hope to the treatment of neurodegenerative diseases.
Establishing the link between CMA and Alzheimer's disease In this study, Cuervo's team first investigated whether damaged CMA can cause Alzheimer's disease.
To this end, they genetically modified a mouse to make the excitatory neurons in the brain lack CMA.
It turned out that the lack of CMA in only one type of brain cell is enough to cause short-term memory loss, walking impairment, and other problems often found in rodent models of Alzheimer's disease.
In addition, in the absence of CMA, protein homeostasis (proteostasis) will be severely disrupted, and this is the cell's ability to regulate the proteins it contains.
Under normal circumstances, soluble proteins become insoluble, with the risk of coagulation into toxic polymers.
Cuerve's reverse suspicion of this phenomenon is also correct: early Alzheimer's disease can also damage CMA.
She and her colleagues studied a mouse model equivalent to early Alzheimer's disease, in which the brain neurons of the mouse can produce defective copies of the tau protein.
There is evidence that this abnormal copy of the tau protein will clump together to form neurofibrillary tangles (neurofibrillary tangles), leading to Alzheimer's disease.
The hippocampus (hippocampus) is an area of the brain that is essential for memory and learning.
The research team focused on the CMA activity in neurons in this area and found that compared with the animals in the control group, the neurons in the diseased mice The CMA activity is significantly reduced.
What about human patients with early Alzheimer's disease? Does it also hinder CMA (of human cells)? In order to find the answer, the researchers performed single-cell RNA sequencing on the brain neurons of Alzheimer's disease patients after death, and compared them with a set of data from a control group of healthy individuals, hoping to understand the role of CMA in the brain tissue of patients.
Activity level.
Sure enough, patients in the early stage of Alzheimer's disease have a certain degree of inhibition of CMA activity; in the late stage of Alzheimer's disease, this inhibition is more serious.
Cuervo said: “When people reach the age of 70 or 80, CMA activity levels are usually reduced by about 30% compared to when they were younger.
Although most people’s brains can compensate for this decline, if neurodegenerative diseases are added at this time This may have a devastating effect on the normal protein composition of brain neurons.
Our research shows that CMA dysfunction and the pathological process of Alzheimer’s disease work synergistically, which will greatly accelerate the development of the disease.
"A kind of "cleaning" "New neuron drug based on this encouraging discovery, Cuervo and his team have developed a new drug that shows the potential to treat Alzheimer's disease.
Cuervo said: "We know that CMA can digest defective tau protein and other proteins.
But in Alzheimer's disease and other neurodegenerative diseases, a large number of defective proteins make CMA overwhelmed and eventually paralyzed.
And we Of drugs can revive the efficiency of CMA by increasing the level of key components of CMA.
"In CMA, a kind of protein called chaperones binds to damaged or defective proteins in the cells of the body, and transports them to the lysosomes of the cell as "cargo".
.
as an internal filled with membrane-bound enzyme organelles, lysosomes and digestion can play a role in waste recycling.
However, in order to successfully these "goods" into lysosomes, chaperones they must first be "docked "referred to LAMP2A receptor protein" docks "on the receptor and this film is long in the lysosomes.
more LAMP2A lysosomal receptors, CMA activity may be higher.
this is The new drug called CA works by increasing the number of LAMP2A receptors.
LAMP2A in neurons participates in autophagy.
Picture source: Courtesy of Albert Einstein College of Medicine The number of bodies is the same.
But these receptors degrade faster than age.
So in the elderly, there are often fewer available receptors to transport unwanted proteins to the lysosome.
CA is a drug that can restore the amount of LAMP2A to a youthful level, allowing CMA to effectively get rid of tau protein and other proteins, so that they will not form those toxic protein clumps.
Also in April, Dr.
Cuervo’s team reported in Nature Communications that they had isolated lysosomes from the brains of Alzheimer’s patients for the first time, and observed a significant increase in the number of LAMP2 receptors.
The reduction will result in the loss of human CMA, as found in animal models. Researchers tested CA in two different mouse models of Alzheimer's disease and found that after 4 to 6 months of oral medication, the memory, depression, and anxiety problems of these two diseased mice were improved and treated The latter mice were the same or almost the same as the healthy control mice.
Cuervo added: "The important thing is that the animals in these two models have shown symptoms of the disease.
Before the drug is administered, their neurons have been blocked by toxic proteins.
This means that the drug can even be Helps maintain neuron function in the later stages of the disease.
Another finding that excites us is that the drug also significantly reduces the phenomenon of gliosis, that is, inflammation and scars around neurons in the brain.
Glial hyperplasia and toxicity Protein is related, and it is currently known to play an important role in the persistence and deterioration of neurodegenerative diseases.
"Research shows that even if CA is taken for a long time and every day, this treatment does not seem to damage other organs.
The drug was designed by Dr.
Evripidis Gavathiotis, a professor of biochemistry and medicine, and co-leader of research.
It is reported that Cuervo and Gavathiotis have partnered with Life Biosciences of Boston, Mass.
to establish Selphagy Therapeutics.
The company is currently developing CA and related compounds for the treatment of Alzheimer's disease and other neurodegenerative diseases.
