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Updated: Jul 12, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer's
Xingyu Zhang1, Li Tang1, Jiaolong Yang1
1Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Abstract:
Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identified transgelin-2 (TG2) expressed on neurons as the receptor for sTREM2. The microglia-derived sTREM2 binds to TG2, induces RhoA phosphorylation at S188, and deactivates the RhoA-ROCK-GSK3β pathway, ameliorating tau phosphorylation. The sTREM2 (77-89) fragment, which is the minimal active sequence of sTREM2 to activate TG2, mimics the inhibitory effect of sTREM2 on tau phosphorylation. Overexpression of sTREM2 or administration of the active peptide rescues tau pathology and behavioral defects in the tau P301S transgenic mice. Together, these findings demonstrate that the sTREM2-TG2 interaction mediates the cross-talk between microglia and neurons. sTREM2 and its active peptide may be a potential therapeutic intervention for tauopathies including AD.
Insights
Soluble TREM2 (sTREM2) from microglia binds neuronal TG2, inhibiting tau phosphorylation. This sTREM2-TG2 pathway offers a potential therapeutic strategy for Alzheimer's disease and other tauopathies.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) shedding produces soluble TREM2 (sTREM2).
- Elevated sTREM2 in cerebrospinal fluid correlates with Alzheimer's disease (AD).
- The role of sTREM2 in AD pathogenesis is not fully understood.
Purpose of the Study:
- To identify the receptor for sTREM2 on neurons.
- To elucidate the mechanism by which sTREM2 influences tau phosphorylation.
- To evaluate the therapeutic potential of sTREM2 in a mouse model of tauopathy.
Main Methods:
- Identified transgelin-2 (TG2) as the neuronal receptor for sTREM2.
- Investigated the effect of sTREM2 binding to TG2 on the RhoA-ROCK-GSK3β pathway.
- Utilized a tau P301S transgenic mouse model to assess the in vivo effects of sTREM2 and its active peptide.
Main Results:
- Microglia-derived sTREM2 binds to neuronal TG2, inhibiting tau phosphorylation via the RhoA-ROCK-GSK3β pathway.
- A minimal active sTREM2 peptide (77-89) mimics these inhibitory effects.
- sTREM2 overexpression or active peptide administration ameliorated tau pathology and cognitive deficits in mice.
Conclusions:
- The sTREM2-TG2 interaction represents a novel cross-talk mechanism between microglia and neurons.
- sTREM2 and its active peptide demonstrate therapeutic potential for tauopathies, including Alzheimer's disease.
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