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Editor-in-Chief | Alzheimer's Disease (Alzheimer's Disease, or Alzheimer's Disease) is a type of neurodegenerative disease that develops and worsens over time.
Its functional decline is usually manifested in the patient's dementia symptoms, including behavioral problems such as gradual loss of short-term memory, language barriers, and inability to take care of themselves, which eventually leads to death.
About 40 million people in the world suffer from Alzheimer's disease.
However, there is no medicine or treatment that can cure or reverse the course of the disease.
One of the hallmark pathological features of Alzheimer's disease is the deposition of Abeta amyloid plaques in the brain.
As early as 1906, German doctor Alois Alzheimer (Alois Alzheimer) and his colleagues identified and discovered this high-density starch-like protein structure.
The true cause of Alzheimer's disease is still unknown.
Microglia are macrophages that reside in the central nervous system.
In recent years, many Genome-Wide Association Studies (GWAS) have shown that many risk factors for Alzheimer’s disease are related to immune genes and are largely specific in microglia.
Expression [1].
This discovery changed the traditional view that Alzheimer's disease is a neuron-centered degenerative disease.
We already know that when amyloid deposits are produced, microglia will tightly gather around plaque deposits and become activated.
However, the mechanism by which microglia can accurately detect Abeta amyloid deposits is still unknown, and the inhibition of some candidate molecular pathways in preclinical studies has little effect on the course of the disease.
Recently, the single-cell RNA sequencing results of these clusters of "disease associate microglia" showed that TAM receptor tyrosine kinases (receptor tyrosine kinases), especially the Axl receptor, had mRNA levels.
Significantly up-regulated in these activated microglia [2].
At the same time, the level of the soluble ectodomain of the Axl receptor in the cerebrospinal fluid has also been shown to be used to predict the occurrence of Alzheimer's disease [3].
The research team of Professor Greg Lemke from the Salk Institute focuses on studying the function of the TAM receptor system.
Previous studies have shown that microglia can recognize and eliminate apoptotic cells in the adult neurogenesis area through TAM receptors [4 ,5].
These findings inspired us to further use the mouse model of Alzheimer's disease to study the role of the TAM receptors Axl and Mer of microglia on the development of degenerative diseases.
On April 15, 2021, Greg Lemke's team (the first author is Dr.
Huang Youtong) published an article Microglia use TAM receptors to detect and engulf amyloid β plaques in Nature Immunology, revealing that Mer and Axl recognize and respond to microglia It plays an important role in the precipitation of Abeta amyloid associated with Alzheimer's disease.
This study showed that TAM receptors and their ligands are the main mediators used by microglia to recognize and swallow the newly formed Abeta amyloid with "loose" tissue structure.
Furthermore, these findings reveal that the process of microglia phagocytosis itself can drive the formation of high-density "dense-core" amyloid (dense-core plaques).
Other related studies have found that if the participation of microglia is inhibited, Abeta amyloid deposits will not be formed in the brains of these Alzheimer's mice, and only the residual microglia will be sporadic.
"Dense core" amyloid deposition [6].
Therefore, part of the formation mechanism of these "dense nuclear" amyloids needs to be organized by microglia (similar to granulomas dominated by macrophages in tuberculosis), and TAM receptors are a necessary part of the molecular mechanism of this process.
one.
Researchers speculate that Abeta that is phagocytosed by microglia may form "dense nuclear" amyloid in acidic environments such as lysosomes in microglia, and be excreted out of the cell by exocytosis or apoptosis in microglia Then a new "dense core" amyloid is formed.
And their formation may be a relatively benign compensation method for the body to cope with and resist the long-term inflammation and neurodegeneration in Alzheimer's disease.
Current clinical trials for Alzheimer’s disease mostly rely on drugs that eliminate these Abeta amyloid structures, including the recently disclosed results of Biogen’s Aducanumab Phase III clinical trial.
These therapies are without exception and have no significant effect on the patient’s cognitive ability.
The improvement failed.
The results of this research reveal from the perspective of neuroimmunity that "dense nucleus" amyloid relies on the formation mechanism of microglia, and may explain the reasons for the failure of these experiments.
At present, small molecule inhibitors of TAM receptors have been used in clinical trials for a variety of cancer treatments.
This study can encourage cancer clinical researchers to evaluate patients with neurodegeneration, and it also provides new targets and directions for the treatment of Alzheimer’s disease, and deepens the effect of microglia in Alzheimer’s.
Understanding of the role of the disease. Original link: https://doi.
org/10.
1038/s41590-021-00913-5 Plate maker: Eleven References 1.
Long, JM & Holtzman, DM Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.
Cell 179, 312-339 (2019).
2.
Keren-Shaul, H.
et al.
A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.
Cell 169, 1276-1290 e1217 (2017) 3.
Mattsson, N.
et al.
CSF protein biomarkers predicting longitudinal reduction of CSF beta-amyloid42 in cognitively healthy elders.
Translational psychiatry 3, e293 (2013).
4.
Fourgeaud, L.
et al.
TAM receptors regulate multiple features of microglial physiology.
Nature 532, 240-244 (2016 ).
5.
Lemke, G.
Biology of the TAM receptors.
Cold Spring Harbor Perspectives 5(11), doi: 10.
1101/cshperspect.
a009076.
(2013).
6.
Spangenberg, E.
et al.
Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.
Nature communications 10, 3758 (2019).
Reprint instructions [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.
Its functional decline is usually manifested in the patient's dementia symptoms, including behavioral problems such as gradual loss of short-term memory, language barriers, and inability to take care of themselves, which eventually leads to death.
About 40 million people in the world suffer from Alzheimer's disease.
However, there is no medicine or treatment that can cure or reverse the course of the disease.
One of the hallmark pathological features of Alzheimer's disease is the deposition of Abeta amyloid plaques in the brain.
As early as 1906, German doctor Alois Alzheimer (Alois Alzheimer) and his colleagues identified and discovered this high-density starch-like protein structure.
The true cause of Alzheimer's disease is still unknown.
Microglia are macrophages that reside in the central nervous system.
In recent years, many Genome-Wide Association Studies (GWAS) have shown that many risk factors for Alzheimer’s disease are related to immune genes and are largely specific in microglia.
Expression [1].
This discovery changed the traditional view that Alzheimer's disease is a neuron-centered degenerative disease.
We already know that when amyloid deposits are produced, microglia will tightly gather around plaque deposits and become activated.
However, the mechanism by which microglia can accurately detect Abeta amyloid deposits is still unknown, and the inhibition of some candidate molecular pathways in preclinical studies has little effect on the course of the disease.
Recently, the single-cell RNA sequencing results of these clusters of "disease associate microglia" showed that TAM receptor tyrosine kinases (receptor tyrosine kinases), especially the Axl receptor, had mRNA levels.
Significantly up-regulated in these activated microglia [2].
At the same time, the level of the soluble ectodomain of the Axl receptor in the cerebrospinal fluid has also been shown to be used to predict the occurrence of Alzheimer's disease [3].
The research team of Professor Greg Lemke from the Salk Institute focuses on studying the function of the TAM receptor system.
Previous studies have shown that microglia can recognize and eliminate apoptotic cells in the adult neurogenesis area through TAM receptors [4 ,5].
These findings inspired us to further use the mouse model of Alzheimer's disease to study the role of the TAM receptors Axl and Mer of microglia on the development of degenerative diseases.
On April 15, 2021, Greg Lemke's team (the first author is Dr.
Huang Youtong) published an article Microglia use TAM receptors to detect and engulf amyloid β plaques in Nature Immunology, revealing that Mer and Axl recognize and respond to microglia It plays an important role in the precipitation of Abeta amyloid associated with Alzheimer's disease.
This study showed that TAM receptors and their ligands are the main mediators used by microglia to recognize and swallow the newly formed Abeta amyloid with "loose" tissue structure.
Furthermore, these findings reveal that the process of microglia phagocytosis itself can drive the formation of high-density "dense-core" amyloid (dense-core plaques).
Other related studies have found that if the participation of microglia is inhibited, Abeta amyloid deposits will not be formed in the brains of these Alzheimer's mice, and only the residual microglia will be sporadic.
"Dense core" amyloid deposition [6].
Therefore, part of the formation mechanism of these "dense nuclear" amyloids needs to be organized by microglia (similar to granulomas dominated by macrophages in tuberculosis), and TAM receptors are a necessary part of the molecular mechanism of this process.
one.
Researchers speculate that Abeta that is phagocytosed by microglia may form "dense nuclear" amyloid in acidic environments such as lysosomes in microglia, and be excreted out of the cell by exocytosis or apoptosis in microglia Then a new "dense core" amyloid is formed.
And their formation may be a relatively benign compensation method for the body to cope with and resist the long-term inflammation and neurodegeneration in Alzheimer's disease.
Current clinical trials for Alzheimer’s disease mostly rely on drugs that eliminate these Abeta amyloid structures, including the recently disclosed results of Biogen’s Aducanumab Phase III clinical trial.
These therapies are without exception and have no significant effect on the patient’s cognitive ability.
The improvement failed.
The results of this research reveal from the perspective of neuroimmunity that "dense nucleus" amyloid relies on the formation mechanism of microglia, and may explain the reasons for the failure of these experiments.
At present, small molecule inhibitors of TAM receptors have been used in clinical trials for a variety of cancer treatments.
This study can encourage cancer clinical researchers to evaluate patients with neurodegeneration, and it also provides new targets and directions for the treatment of Alzheimer’s disease, and deepens the effect of microglia in Alzheimer’s.
Understanding of the role of the disease. Original link: https://doi.
org/10.
1038/s41590-021-00913-5 Plate maker: Eleven References 1.
Long, JM & Holtzman, DM Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.
Cell 179, 312-339 (2019).
2.
Keren-Shaul, H.
et al.
A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.
Cell 169, 1276-1290 e1217 (2017) 3.
Mattsson, N.
et al.
CSF protein biomarkers predicting longitudinal reduction of CSF beta-amyloid42 in cognitively healthy elders.
Translational psychiatry 3, e293 (2013).
4.
Fourgeaud, L.
et al.
TAM receptors regulate multiple features of microglial physiology.
Nature 532, 240-244 (2016 ).
5.
Lemke, G.
Biology of the TAM receptors.
Cold Spring Harbor Perspectives 5(11), doi: 10.
1101/cshperspect.
a009076.
(2013).
6.
Spangenberg, E.
et al.
Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.
Nature communications 10, 3758 (2019).
Reprint instructions [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be investigated.
