Cell: Focusing on the role of SYK-dependent and non-dependent pathways in microglia in Alzheimer's disease

Recently, Professor Marco Colonna's team from the Department of Pathology and Immunology at the University of Washington School of Medicine published a study entitled "lTREM2 drives microglia response to amyloid-β via SYK-dependent and -independent paths" online in the journal Cell.
Demonstrated that microglia respond
to Ab by activating TREM2-mediated Syk and DAP10 signaling mechanisms.
In mice expressing the Alzheimer's disease-associated human TREM2R47H allele, antibody-mediated Syk activation rescued microglial activation
。 A few days ago, the team of John R.
Lukens of the Center for Brain Immunology and Glial Cells in the Department of Neuroscience at the University of Virginia published an article "SYK coordinates neuroprotective microglial responses in neurodegenerative disease" in the journal Cell in October 2022, which pointed out that SYK regulates the activation and function of microglia.
Impaired function is associated
with worsening of neurodegenerative disease models such as Alzheimer's disease and multiple sclerosis.

The coding gene for SYK is syk, cloned from porcine spleen cDNA in 1991, and the protein encoded is a member of the non-receptor tyrosine kinase Src family, which can catalyze the phosphorylation of the substrate protein tyrosine residue, so it is named spleen tyrosine kinase (Spleen Tyrosine Kinase
).

Brainnews interpreted the literature yesterday, click to view:

Cell: A novel mechanism by which microglia lead to increased Aβ deposition in Alzheimer's disease, neuropathological exacerbation, and cognitive deficits

Microglia attached to Aβ plaques acquire a transcriptional marker, the "disease-associated microglia" (DAM), which is primarily derived from the TREM2-DAP12 receptor complex that transmits intracellular signals via the protein tyrosine kinase SYK
.
The TREM2 R47H variant in people associated with high AD risk cannot activate microglia
via SYK.
The researchers found that SYK-deficient microglia were unable to wrap Aβ plaques, which accelerated brain pathological progression and behavioral deficits
.

The authors first tested whether Aβ accumulation would activate SYK
in microglia.
SYK phosphorylation increased in microglia from 5xFAD mice, while the total amount of SYK protein did not change
.
After specifically knocking out the expression of Syk gene in microglia using gene knockout technology, it was found that SYK deletion led to significantly reduced microglial proliferation, significantly reduced density, and more
fibrous Aβ deposition.

Further studies by the authors confirmed that SYK deficiency in microglia is associated with
an increase in Aβ pathology, neuronal damage, and behavioral deficits.
Aβ1–42 deposition increased significantly in SYK-deficient mice, and neuronal atrophy increased
.
The results of the water maze test confirmed that the lack of SYK in microglia accelerated memory impairment
in 5xFAD mice.
The elevated maze test found that SYK-deficient mice entered significantly more times in the open arm and walked longer
distances.
Therefore, it was concluded that the deficiency of SYK in microglia exacerbated the load of Aβ1–42 and the damage of neurons, worsening behavioral defects
.

In addition, the authors found that the deficiency of SYK led to reduced phosphorylation of AKT and its targets NDRG1 and GSK-3β, which are associated
with mTOR activation, protein synthesis, and cell cycle progression.
Microglia in SYK-deficient mice also had significant loss of mitochondrial quality
.
Further biochemical analysis revealed metabolic defects in SYK-deficient mice with increased autophagy
.
At the same time, by inducing mice that had antibody deposition and microglia to knock out the SYK gene, it was shown that SYK is necessary
to maintain microglia aggregation around antibody plaques after the onset of the disease.

Next, the authors also analyzed the effect
of SYK deficiency on the transcriptome of microglia during amyloid pathology.
TREM2+, CLEC7A+, CD11c+, and CD74+ microglia were significantly reduced in SYK-deficient mice, while TMEM119+ microglia were increased
.
These changes are particularly pronounced in microglia near the antibody plaque, while SYK deficiency has little
effect on microglia distal to the antibody plaque.
GSEA that also differentially expressed genes suggests that metabolic pathways are highly influenced
by SYK deficiency.

Under pathological conditions, impaired energy metabolism due to SYK deletion significantly affects microglial activation, i.
e.
, at the molecular level, cells are not able to fully differentiate and thus obtain characteristics
of DAM, MHC II, IFN-R MICROGLIA GENE EXPRESSION.
However, SYK deficiency does not affect microglial proliferation compared to TREM2 deficiency and allows microglia to be activated to a lesser extent, acquiring partial characteristics of DAM
.
This suggests that TREM2 can partially activate microglia
independently of SYK.

Previous studies have shown that the TREM2-DAP12 complex regulates ERK activation through a SYK-independent
pathway.
The authors also confirmed that microglial phenotype-induced SYK deficiency was not associated with
any signaling dependent on the TREM2-DAP12 axis.
In addition to DAP12, TREM2 binds to the transmembrane linker DAP10 in BMDM, and the authors confirmed that the DAP10 signaling pathway maintains microglial proliferation, metabolic activation, survival, and Aβ phagocytosis independently of SYK, which are all required for
complete microglial activation.

The authors also explored the possibility
of using SYK as an activating punctuation point for the treatment of AD.
CLEC7A is a class of surface receptors that directly recruit and activate SYK and are upregulated
in microglia during neurodegeneration.
The authors demonstrated that systemic administration of agonist anti-CLEC7A antibodies to 5xFAD mice carrying the dysfunctional TREM2R47H variant promoted SYK signaling and improved microglial activation
.

Finally, the authors mined the SnRNA-seq data of human AD and compared the expression of SYK and CLEC7A mRNA using TREM2, confirming that SYK and CLEC7A were highly expressed
in microglia of AD.
Therefore, the CLEC7A-SYK pathway in microglia may be a potential target for the treatment of
AD.

Summary

In summary, this study verifies for the first time the effects of SYK and DAP10 signaling on the amyloid pathological response of microglia, and proposes a new CLEC7A treatment, which has great application value
for AD research.
On this basis, further research
can be carried out on how these pathways coordinate the function of microglia in the future.