-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Responsible editor | Xi
It murders the happiness of countless families, makes loved ones strangers, and brings endless pain and heavy burdens
to families.
It is Alzheimer's disease (AD), commonly known as Alzheimer's disease or dementia
.
Alzheimer's disease is a chronic brain disease that gradually destroys the patient's memory and thinking ability, damages brain tissue, and eventually leads to death
.
For most elderly patients with dementia, symptoms begin to appear in later life, and once clinical symptoms appear, it will greatly interfere with the patient's daily activities, significantly reduce the patient's quality of life, and bring huge costs
to the sick family and the health care system.
However, so far, researchers have not found effective means to treat or delay the onset and progression
of Alzheimer's disease.
On October 27, 2022, Marco Colonna's research group from Washington University in St.
Louis published the TREM2 Drives Microglia Response to Amyloid-β via SYK-dependent and -independent Paths in Cell research paper (first author is Dr.
Wang Shoutang).
The paper provides a theoretical basis
for finding new ways to effectively treat early AD.
The pathogenesis of AD is not well understood
.
Currently, the most accepted explanation for AD pathology is the amyloid cascade hypothesis
.
It has been hypothesized that the aggregation and deposition of amyl β oid b (Ab) peptides outside the cell by amyloid b (Ab) peptides produced by neurons is a key pathogenic process
in AD.
This process leads to the formation of amyloid plaques, as well as neurofibrillary tangles, neuronal cell death, synaptotropy, and dementia
.
Recent studies have shown that microglia play an extremely important role
in controlling and delaying this pathogenic process.
Microglia are a type of glial cell
found throughout the central nervous system of the brain.
These cells act as the main macrophages in the brain, involved in the defense of clearing lesions of the cerebral nervous system and repairing
damage.
In the early AD pathogenic process, microglia are able to recognize amyloid plaques and rapidly aggregate around the plaque lesions to form a physical barrier, thereby preventing further spread
of neurotoxic fibrils around the plaques.
At the same time, microglia can also exert its phagocytosis, remove the deposition of amyloid plaques, and slow the progression
of the disease.
Previous research by the group demonstrated that these microglia respond to amyloid plaques relying on a specific class of cell surface receptors expressed on myeloid cells 2
。 When TREM2 receives an extracellular stimulus signal, the cell passes its immune receptor tyrosine-based activation motif (ITAM) through its adapter DAP12 The protein tyrosine kinase SYK is recruited and activated, and the activated SYK further activates the downstream related signaling pathway, completing the transduction of extracellular signals into the cell and activating the expression
of related response genes.
At the molecular level, high-throughput single-cell RNA-sequencing (scRNA-seq) analysis studies have shown that microglia respond to amyloid plaques to activate into 4 functionally distinct cell populations, i.
e.
, disease-related, based on differences in transcriptome expression levels (disease-associated microglia, DAM), MHC II microglia, interferon-reactive (IFN-R microglia), and proliferative microglia (cycling microglia)
。 This series of activation processes is directly regulated by TREM2, implying that TREM2 plays a key regulatory role
in microglia-controlled pathogenic processes.
It is worth noting that the protein tyrosine kinase SYK in cells can also be activated by many other DAM-related cell surface receptors, such as CLEC7A (C-type lectin domain family 7 member A), integrins, etc
。 Therefore, SYK's effect on microglial responses to pathogenic stimuli may be more extensive
than TREM2.
In order to test this hypothesis, in this paper, using gene knockout technology to specifically knock out the expression of the Syk gene in microglia, the authors first demonstrated that in the mouse model of Ab accumulation, microglia lacking SYK are unable to activate in response to brain parenchymal lesions and wrap Ab aggregates, resulting in increased accumulation of Ab plaques in the brain parenchyma of mutant mice.
This led to the formation of more malnourished neurites that exacerbated the defects
in mouse behavior.
In addition, it was observed by immunoblotting, immunofluorescence staining of brain slices, flow cytometry, and transmission electron microscopy (transmission electron microscope), the authors found that the lack of SYK impairs the cell's PI3K-AKT-GSK3b signaling pathway, leading to defects in mTOR signaling, which disrupts the energy and anabolic support
that provides cell activation 。 Through scRNA-seq analysis, the authors note that under pathological conditions, impaired energy metabolism caused by SYK deletion significantly affects the activation of microglia, i.
e.
, at the molecular level, cells are not able to fully differentiate to obtain the characteristics
of DAM, MHC II, IFN-R microglial gene expression.
Surprisingly, however, the lack of SYK did not affect the proliferation of microglia compared to the lack of TREM2 and allowed microglia to activate to a lower extent, acquiring the characteristics
of some DAM.
This suggests that TREM2 can activate microglia
independently of the SYK moiety.
The authors went on to further demonstrate that microglia-activated TREM2-dependent, the DAP12-SYK independent pathway is done by
DAP10-mediated.
DAP10 is a DAP12-related adapter whose activation does not recruit and activate the SYK protein, but binds
directly to PI3K.
Finally, the authors explore the possibility
of using SYK as an activation punctuation point for the treatment of AD.
As mentioned above, CLEC7A is a class of surface receptors
that directly recruit and activate SYK.
Specifically expressed
in the central nervous system only in microglia.
Thus, in an animal model of AD with partial loss of TREM2 function, the authors observed that intraperitoneal injection of monoclonal antibodies specifically bound to CLEC7A rescued the activation of microglia that were defective in response to Ab
plaques.
What's more, similar to the data obtained from animal models, the authors found that CLEC7A and SYK were highly expressed in AD microglia by examining a high-throughput single-nucleus RNA-sequencing (snRNA-seq) database of postmortem brain tissue specimens from patients.
Implicit use of CLEC7A agonist to activate microglia activation as a treatment for early ADPossibilities
.
Overall, this study has made great progress in understanding and perfecting the TREM2-mediated signaling pathway in microglia under pathological conditions of AD, and on this basis, a new AD treatment method is proposed, which has great application value
.
Original link:
https://doi.
org/10.
1016/j.
cell.
2022.
09.
033
Pattern maker: Eleven
Reprint instructions
【Non-original article】The copyright of this article belongs to the author of the article, personal forwarding and sharing is welcome, reprinting is prohibited without the permission of the author, the author has all legal rights, and violators must be investigated
.
