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This experimental drug can reverse the key symptoms of Alzheimer's disease in mice without damaging other organs.
Alzheimer's disease is a neurodegenerative disease with insidious onset and progressive development, with clinical features Mainly are cognitive impairment, abnormal mental behavior and decline of social life function.
Generally, the onset is early onset before the age of 65 and late onset after the age of 65.
A family tendency is called familial Alzheimer's disease, and no family tendency is called sporadic Alzheimer's disease.
According to the World Health Organization, about 50 million people worldwide suffer from dementia, of which Alzheimer's disease is the most common type.
Possible risk factors for Alzheimer's disease include: increasing age, women, low education level, smoking, middle-aged hypertension and obesity, hearing impairment, brain trauma, lack of exercise, social loneliness, diabetes, and depression.
In a new study, researchers from the Albert Einstein School of Medicine in the United States designed an experimental drug that can reverse the key symptoms of Alzheimer's disease in mice.
The drug works by reactivating a protein that is not needed for digestion and recycling to remove their cell cleansing mechanism.
The relevant research results were published online in Cell on April 22, 2021.
The title of the paper is "Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome".
The researchers said that the findings made in mice are not always applicable to humans, especially in Alzheimer’s disease, but they found that the decrease in cell cleaning ability that leads to Alzheimer’s disease mouse models also occurs in this area.
In patients with the disease, this suggests that the drug may also work in humans.In the 1990s, Dr.
Ana Maria Cuervo, co-director of the Institute of Aging at the Albert Einstein School of Medicine, discovered this cell cleansing process called chaperone-mediated autophagy (CMA).
So far, 200 papers have been published on its role in health and disease.
As people age, the efficiency of CMA becomes lower and lower, which increases the risk of unwanted proteins accumulating into insoluble clumps that damage cells.
In fact, Alzheimer’s disease and all other neurodegenerative diseases are characterized by the presence of toxic protein aggregates in the patient’s brain.
In this study, these authors revealed the dynamic interaction between CMA and Alzheimer's disease.
Loss of CMA in neurons can promote Alzheimer's disease and vice versa.
These findings indicate that drugs that activate CMA may offer hope for the treatment of neurodegenerative diseases.
Researchers first studied whether damage to CMA can cause Alzheimer's disease.
To this end, they genetically modified mice to have excitatory brain neurons that lack CMA.
This lack of CMA in brain cells is sufficient to cause short-term memory loss, walking impairment, and other problems often found in rodent models of Alzheimer's disease.
In addition, the lack of CMA greatly disrupts protein homeostasis (proteostasis)-the ability of cells to regulate the proteins they contain.
Under normal circumstances, soluble proteins have become insoluble, and there is a risk of forming toxic aggregates.
Activating CMA can maintain protein homeostasis and resist protein toxicity.
The picture is from Cell, 2021, doi:10.
1016/j.
cell.
2021.
03.
048.
Researchers speculate that the reverse is also true: Early Alzheimer's disease can damage CMA.
Therefore, they studied a mouse model of early Alzheimer's disease, in which brain neurons were modified to produce defective versions of the tau protein.
There is evidence that abnormal versions of tau protein clump together to form neurofibrillary tangles, which can lead to Alzheimer's disease.
They focused on the CMA activity in neurons in the hippocampus, where the hippocampus is a brain area that is essential for memory and learning.
They found that in this mouse model, the CMA activity in these neurons was significantly reduced compared to control mice.
Will early human Alzheimer's disease also block CMA? To find out, the authors looked at single-cell RNA sequencing data of neurons obtained from the post-mortem brains of Alzheimer's disease patients and healthy people.
These sequencing data showed the activity level of CMA in the patient's brain tissue.
Sure enough, in the early stages of Alzheimer's disease, the activity of CMA was inhibited to a certain extent, and then in the brains of patients with advanced Alzheimer's disease, CMA was inhibited much more.
When people reach 70 or 80 years of age, CMA activity is usually about 30% less than when they were younger.
Most people's brains can compensate for this decline.
However, if neurodegenerative diseases are added, the effect on the normal protein composition of brain neurons can be devastating.
These authors found that the lack of CMA has a synergistic effect with the pathology of Alzheimer's disease, thereby greatly accelerating the progression of the disease.
In one of the encouraging findings, researchers have developed a new type of drug that has shown the potential to treat Alzheimer's disease.
They know that CMA can degrade defective tau and other proteins, but the large number of defective proteins in Alzheimer's disease and other neurodegenerative diseases overwhelms CMA and basically paralyzes it.
This drug re-enhance the efficiency of CMA by increasing the level of a key CMA component.
In CMA, proteins called chaperones bind to damaged or defective proteins in cells in the body.
Molecular chaperones transport their cargo to the lysosome of the cell.
The lysosome is a membrane organelle that contains enzymes that digest and recycle waste.
However, in order to successfully deliver the cargo they carry into the lysosome, the chaperone must first "dock" the cargo to a protein receptor called LAMP2A, which grows from the membrane of the lysosome.
The more LAMP2A receptors on the lysosome, the higher the level of potential CMA activity.
This new drug called CA works by increasing the number of these LAMP2A receptors.
Researchers say that people produce the same number of LAMP2A receptors in their lifetime, but these receptors degrade faster with age, so older people tend to have fewer receptors for delivery of unwanted proteins.
To the lysosome.
CA restores LAMP2A to youthful levels, allowing CMA to remove defective tau and other defective proteins so that they cannot form toxic protein clumps.
[These researchers reported for the first time in the journal Nature Communications this month that they isolated lysosomes from the brains of Alzheimer’s disease patients and observed that the decrease in the number of LAMP2 receptors led to the loss of CMA in humans, just like in As observed in animal models of Alzheimer’s disease (Nature Communications, 2021, doi:10.
1038/s41467-021-22501-9).
] The researchers tested CA in two different mouse models of Alzheimer's disease.
In these two mouse models, oral doses of CA given over a period of 4 to 6 months can improve memory, depression and anxiety, making the treated mouse model look like or very much like healthy control mice .
In a mouse model with problems with walking ability, this walking ability was significantly improved.
And in the brain neurons of the two mouse models, the drug significantly reduced the levels of tau protein and protein clumps compared with untreated mice.
Importantly, both of these mouse models had symptoms of disease, and their neurons had been blocked by toxic proteins before the medication.
This means that the drug may help protect neuronal function, even in the later stages of the disease.
Researchers are also very excited that the drug significantly reduces gliosis, which is inflammation and scar formation in cells surrounding neurons in the brain.
Glial hyperplasia is related to toxic proteins and is known to play an important role in perpetuating and exacerbating neurodegenerative diseases.
Treatment with CA does not seem to damage other organs, even when administered daily for a longer period of time.
Researchers are currently developing CA and related compounds for the treatment of Alzheimer's disease and other neurodegenerative diseases.
References: 1.
Mathieu Bourdenx et al.
Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.
Cell, 2021, doi:10.
1016/j.
cell.
2021.
03.
048.
2.
Benjamin Caballero et al.
Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.
Nature Communications, 2021, doi:10.
1038/s41467-021-22501-9.
Alzheimer's disease is a neurodegenerative disease with insidious onset and progressive development, with clinical features Mainly are cognitive impairment, abnormal mental behavior and decline of social life function.
Generally, the onset is early onset before the age of 65 and late onset after the age of 65.
A family tendency is called familial Alzheimer's disease, and no family tendency is called sporadic Alzheimer's disease.
According to the World Health Organization, about 50 million people worldwide suffer from dementia, of which Alzheimer's disease is the most common type.
Possible risk factors for Alzheimer's disease include: increasing age, women, low education level, smoking, middle-aged hypertension and obesity, hearing impairment, brain trauma, lack of exercise, social loneliness, diabetes, and depression.
In a new study, researchers from the Albert Einstein School of Medicine in the United States designed an experimental drug that can reverse the key symptoms of Alzheimer's disease in mice.
The drug works by reactivating a protein that is not needed for digestion and recycling to remove their cell cleansing mechanism.
The relevant research results were published online in Cell on April 22, 2021.
The title of the paper is "Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome".
The researchers said that the findings made in mice are not always applicable to humans, especially in Alzheimer’s disease, but they found that the decrease in cell cleaning ability that leads to Alzheimer’s disease mouse models also occurs in this area.
In patients with the disease, this suggests that the drug may also work in humans.In the 1990s, Dr.
Ana Maria Cuervo, co-director of the Institute of Aging at the Albert Einstein School of Medicine, discovered this cell cleansing process called chaperone-mediated autophagy (CMA).
So far, 200 papers have been published on its role in health and disease.
As people age, the efficiency of CMA becomes lower and lower, which increases the risk of unwanted proteins accumulating into insoluble clumps that damage cells.
In fact, Alzheimer’s disease and all other neurodegenerative diseases are characterized by the presence of toxic protein aggregates in the patient’s brain.
In this study, these authors revealed the dynamic interaction between CMA and Alzheimer's disease.
Loss of CMA in neurons can promote Alzheimer's disease and vice versa.
These findings indicate that drugs that activate CMA may offer hope for the treatment of neurodegenerative diseases.
Researchers first studied whether damage to CMA can cause Alzheimer's disease.
To this end, they genetically modified mice to have excitatory brain neurons that lack CMA.
This lack of CMA in brain cells is sufficient to cause short-term memory loss, walking impairment, and other problems often found in rodent models of Alzheimer's disease.
In addition, the lack of CMA greatly disrupts protein homeostasis (proteostasis)-the ability of cells to regulate the proteins they contain.
Under normal circumstances, soluble proteins have become insoluble, and there is a risk of forming toxic aggregates.
Activating CMA can maintain protein homeostasis and resist protein toxicity.
The picture is from Cell, 2021, doi:10.
1016/j.
cell.
2021.
03.
048.
Researchers speculate that the reverse is also true: Early Alzheimer's disease can damage CMA.
Therefore, they studied a mouse model of early Alzheimer's disease, in which brain neurons were modified to produce defective versions of the tau protein.
There is evidence that abnormal versions of tau protein clump together to form neurofibrillary tangles, which can lead to Alzheimer's disease.
They focused on the CMA activity in neurons in the hippocampus, where the hippocampus is a brain area that is essential for memory and learning.
They found that in this mouse model, the CMA activity in these neurons was significantly reduced compared to control mice.
Will early human Alzheimer's disease also block CMA? To find out, the authors looked at single-cell RNA sequencing data of neurons obtained from the post-mortem brains of Alzheimer's disease patients and healthy people.
These sequencing data showed the activity level of CMA in the patient's brain tissue.
Sure enough, in the early stages of Alzheimer's disease, the activity of CMA was inhibited to a certain extent, and then in the brains of patients with advanced Alzheimer's disease, CMA was inhibited much more.
When people reach 70 or 80 years of age, CMA activity is usually about 30% less than when they were younger.
Most people's brains can compensate for this decline.
However, if neurodegenerative diseases are added, the effect on the normal protein composition of brain neurons can be devastating.
These authors found that the lack of CMA has a synergistic effect with the pathology of Alzheimer's disease, thereby greatly accelerating the progression of the disease.
In one of the encouraging findings, researchers have developed a new type of drug that has shown the potential to treat Alzheimer's disease.
They know that CMA can degrade defective tau and other proteins, but the large number of defective proteins in Alzheimer's disease and other neurodegenerative diseases overwhelms CMA and basically paralyzes it.
This drug re-enhance the efficiency of CMA by increasing the level of a key CMA component.
In CMA, proteins called chaperones bind to damaged or defective proteins in cells in the body.
Molecular chaperones transport their cargo to the lysosome of the cell.
The lysosome is a membrane organelle that contains enzymes that digest and recycle waste.
However, in order to successfully deliver the cargo they carry into the lysosome, the chaperone must first "dock" the cargo to a protein receptor called LAMP2A, which grows from the membrane of the lysosome.
The more LAMP2A receptors on the lysosome, the higher the level of potential CMA activity.
This new drug called CA works by increasing the number of these LAMP2A receptors.
Researchers say that people produce the same number of LAMP2A receptors in their lifetime, but these receptors degrade faster with age, so older people tend to have fewer receptors for delivery of unwanted proteins.
To the lysosome.
CA restores LAMP2A to youthful levels, allowing CMA to remove defective tau and other defective proteins so that they cannot form toxic protein clumps.
[These researchers reported for the first time in the journal Nature Communications this month that they isolated lysosomes from the brains of Alzheimer’s disease patients and observed that the decrease in the number of LAMP2 receptors led to the loss of CMA in humans, just like in As observed in animal models of Alzheimer’s disease (Nature Communications, 2021, doi:10.
1038/s41467-021-22501-9).
] The researchers tested CA in two different mouse models of Alzheimer's disease.
In these two mouse models, oral doses of CA given over a period of 4 to 6 months can improve memory, depression and anxiety, making the treated mouse model look like or very much like healthy control mice .
In a mouse model with problems with walking ability, this walking ability was significantly improved.
And in the brain neurons of the two mouse models, the drug significantly reduced the levels of tau protein and protein clumps compared with untreated mice.
Importantly, both of these mouse models had symptoms of disease, and their neurons had been blocked by toxic proteins before the medication.
This means that the drug may help protect neuronal function, even in the later stages of the disease.
Researchers are also very excited that the drug significantly reduces gliosis, which is inflammation and scar formation in cells surrounding neurons in the brain.
Glial hyperplasia is related to toxic proteins and is known to play an important role in perpetuating and exacerbating neurodegenerative diseases.
Treatment with CA does not seem to damage other organs, even when administered daily for a longer period of time.
Researchers are currently developing CA and related compounds for the treatment of Alzheimer's disease and other neurodegenerative diseases.
References: 1.
Mathieu Bourdenx et al.
Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.
Cell, 2021, doi:10.
1016/j.
cell.
2021.
03.
048.
2.
Benjamin Caballero et al.
Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.
Nature Communications, 2021, doi:10.
1038/s41467-021-22501-9.
