Recently, a team of professors from the Department of Immunology of the University of Washington School of Medicine published a study titled "lTREM2 drives microglia response to amyloid-β via SYK-dependent and -independent paths" in the journal Cell, demonstrating that microglia cells respond to Ab by activating the TREM2-mediated Syk and DAP10 signaling mechanism. Antibody-mediated Syk activation rescued microglia activation in mice expressing the Alzheimer's disease -related human TREM2R47H allele.
A few days ago, the Center for Brain Immunology and Glial Cells Department of Neuroscience at the University of Virginia, USA, JohnR.Lukens team published an article in the journal Cell in October 2022 in the journal Cell. The article pointed out that SYK regulates the activation and function of microglia, and its impaired function is related to the worsening of neurodegenerative disease models such as Alzheimer's disease and multiple sclerosis. The encoding gene of
SYK is cloned from pig spleen cDNA in 1991. The encoded protein is a member of the Src family of non-receptor tyrosine kinases. It can catalyze the phosphorylation of tyrosine residues of substrate proteins, so it is named Spleen Tyrosine kinase (Spleen Tyrosine Kinase).
BrainnewsExplanation of literature yesterday:
Cell: A new mechanism of microglia leading to the intensified Aβ deposition, exacerbation of neuropathological deficiencies in Alzheimer's disease
Microglia attached to Aβ plaque will obtain a transcription marker, namely "Disease-associated microglia" (DAM) , which mainly originates from the TREM2-DAP12 receptor complex that transmits intracellular signals through protein tyrosine kinase SYK. The TREM2 R47H variant associated with high AD risk cannot activate microglia by SYK. The researchers found that SYK-deficient microglia were unable to wrap Aβ plaques, which accelerated brain pathological progression and behavioral deficits.
The author first tested whether Aβ accumulation activates SYK in microglia. SYK phosphorylation increased in glial cells of 5xFAD mice, while the total amount of SYK protein did not change. After using gene knockout technology to specifically knock out the expression of Syk gene in microglia, it was found that SYK deletion caused significantly reduced microglia hyperplasia, significantly reduced density, and more fibrous Aβ deposition.
The author further studies confirmed that the lack of SYK in microglia is associated with the increase in Aβ pathology, neuronal damage and behavioral defects. Aβ1–42 deposition in SYK-deficient mice was significantly increased and neuronal atrophy increased. Results from the water maze test confirmed that the lack of SYK in microglia accelerated memory disorders in 5xFAD mice. Elevated maze tests found that SYK-deficient mice entered significantly more times in the open arms and walked longer. It is therefore concluded that the lack of SYK in microglia exacerbates the load of Aβ1–42 and the damage to neurons, which worsens the behavioral defect.
In addition, the authors found that the lack of SYK results in reduced phosphate of AKTh and its targets NDRG1 and GSK-3β, which is related to mTOR activation, protein synthesis and cell cycle progression. Microglia in SYK-deficient mice also had significant mitochondrial mass decline. Further biochemical analysis showed that SYK-deficient mice had metabolic defects and autophagy and increased. At the same time, knocking out the SYK gene in mice that have already developed antibody deposition and microglia suggests that SYK is necessary to maintain microglia aggregation around antibody plaques after the onset of the disease.
Next, the authors also analyzed the effects of SYK deficiency on the microglia transcriptome during amyloid pathology. TREM2+, CLEC7A+, CD11c+ and CD74+ microglia were found to be significantly reduced in SYK-deficient mice, while TMEM119+ microglia increased.These changes are particularly evident in microglia near antibody plaques, whereas SYK deficiency has little effect on microglia distal to antibody plaques. GSEA, which simultaneously differentially expressed genes, showed that the metabolic pathway was highly affected by SYK deficiency.
Under pathological conditions, impaired energy metabolism caused by SYK loss significantly affects the activation of microglia, that is, at the molecular level, the cells cannot completely differentiate to obtain the characteristics of DAM, MHC II, IFN-R microglia gene expression. However, compared with the lack of TREM2, the lack of SYK did not affect the proliferation of microglia and allowed the microglia to be activated to a lower extent, obtaining the characteristics of partial DAM. This suggests that TREM2 can activate microglia independently of SYK. Previous studies have shown that TREM2-DAP12 complex regulates ERK activation through a SYK-independent pathway. The authors also demonstrated that microglia phenotype-induced SYK deficiency is not associated with any signal dependent on the TREM2-DAP12 axis. In addition to DAP12, TREM2 also binds to the transmembrane linker DAP10 in BMDM. The authors of confirmed that the DAP10 signaling pathway maintains microglia proliferation, metabolic activation, survival and Aβ phagocytosis independently of SYK, which are all necessary for the complete activation of microglia.
The author also explored the possibility of using SYK as activation punctuation for the treatment of AD. CLEC7A is a class of surface receptors that directly recruit and activate SYK and upregulate in microglia during neurodegeneration. The authors demonstrate that systematic administration of agonistic anti-CLEC7A antibodies to 5xFAD mice carrying the hypofunctioning TREM2R47H variant can promote SYK signaling and improve microglia activation.
Finally, the authors mined SnRNA-seq data of human AD and compared the expression of SYK and CLEC7A mRNA using TREM2, confirming that SYK and CLEC7A are highly expressed in microglia in AD. Therefore, the CLEC7A-SYK pathway in microglia may be a potential target for the treatment of AD.
Summary
In summary, the study verified for the first time the impact of SYK and DAP10 signals on microglia on amyloid pathological response, and proposed a new CLEC7A treatment method, which has very important application value for AD research. Based on this, further research can be carried out on how these pathways coordinate the functions of microglia in the future.
Original link:
https://doi.org/10.1016/j.cell.2022.09.033
References:
Wang et al., lTREM2 drives microglia response to amyloid-b via SYK-dependent and -independent paths, Cell (2022),
Compiled by: Leo Ray (brainnews creative team)
review: Simon (brainnews editorial department)
