Soluble TREM2 Ameliorates Tau Pathology in Alzheimer's Disease: Insights from Preclinical Research Empowered by ANT BIO PTE. LTD.

Alzheimer's disease (AD), a devastating neurodegenerative disorder, poses a growing global health challenge with its progressive cognitive decline, memory impairment, and behavioral abnormalities. While the pathological hallmarks of AD—extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein—are well established, the underlying molecular mechanisms driving disease progression remain incompletely understood. Microglia, the resident immune cells of the central nervous system (CNS), have emerged as key regulators in AD pathogenesis through complex cell-cell signaling crosstalk with neurons. A pivotal study published in Nature Communications sheds new light on the role of soluble TREM2 (sTREM2), a secreted form of the myeloid cell receptor TREM2, in mitigating tau pathology and cognitive deficits, identifying Transgelin-2 (TG2) as its critical neuronal receptor. Notably, multiplex fluorescence immunohistochemistry (mIHC) kits from the Absin product line of ANT BIO PTE. LTD. played an indispensable role in validating the spatial colocalization of key molecules, providing foundational evidence for the proposed sTREM2-TG2 signaling axis.

1. Literature Information

•         Title: Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease

•         Journal: Nature Communications

•         Publication Date: October 21, 2023

•         DOI: 10.1038/s41467-023-42505-x

•         Research Team: Zhentao Zhang’s team from Renmin Hospital of Wuhan University

•         Core Reagents from ANT BIO PTE. LTD.: Multiplex Fluorescence IHC Staining Kits (Absin product line), including 4-color to 7-color plus kits (e.g., Catalog No.: abs50012, abs50015) and supporting reagent Antibody Elution Buffer (mIHC-Specific, Catalog No.: abs994)

•         Related Product Link: AntBio - Fueling Research, Feeding Discovery

2. Research Background

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2), a transmembrane receptor exclusively expressed on myeloid cells such as microglia, has been genetically linked to AD risk—rare variants of TREM2 increase AD susceptibility by 2-3 fold. However, the specific role of its soluble form, sTREM2, in regulating tau phosphorylation and cognitive function in AD remained elusive. Prior studies indicated that sTREM2 modulates neuroinflammation and neuronal survival, but its neuronal receptor and downstream signaling pathways in tau pathology had not been identified. This research aimed to address these critical gaps, with the overarching goal of identifying novel therapeutic targets and interventions for tauopathies including AD.

3. Research Strategy

The research team employed a comprehensive, multi-tiered experimental approach integrating in vitro, ex vivo, and in vivo models to systematically dissect the mechanism of sTREM2 in AD:

1.       In Vitro Mechanistic Exploration: Established a HEK293 cell line stably overexpressing GFP-Tau to evaluate the effect of sTREM2 on tau phosphorylation and the involvement of glycogen synthase kinase 3β (GSK3β), a key kinase mediating tau hyperphosphorylation.

2.       Receptor Identification: Utilized Fc-tagged recombinant sTREM2 for affinity purification combined with Western blotting and mass spectrometry to identify sTREM2-interacting proteins in SH-SY5Y cell membranes, focusing on potential neuronal receptors.

3.       Spatial Colocalization Validation: Employed multiplex fluorescence IHC (using ANT BIO PTE. LTD.’s Absin kits) to confirm the colocalization of sTREM2, TG2, and neuronal/glial markers (e.g., MAP2) in brain sections from AD patients and tau P301S transgenic mice.

4.       Functional Validation of TG2: Used shRNA-mediated TG2 knockdown in HEK293-tau cells and primary neurons to verify the necessity of TG2 for sTREM2’s effects on tau phosphorylation; further explored downstream signaling pathways (RhoA-ROCK-GSK3β axis).

5.       In Vivo Efficacy Assessment: Intracerebrally injected AAV-EGFP-sTREM2 into 3-month-old tau P301S mice to evaluate improvements in tau pathology, synaptic integrity, and cognitive function at 7 months of age.

6.       Peptide Mimetic Development: Synthesized sTREM2-derived short peptides, identified the active fragment (residues 77-89), and assessed its brain penetrability and therapeutic efficacy in tau P301S mice via intraperitoneal injection.

4. Key Research Findings

4.1 sTREM2 Inhibits Tau Hyperphosphorylation In Vitro via Suppressing GSK3β Activity

Treatment of GFP-Tau-overexpressing HEK293 cells with sTREM2 (40 nM) significantly reduced tau phosphorylation at key residues (S202, S396, T181, S404), with the most pronounced reductions observed at S202 and S396. This inhibitory effect was dose-dependent. Mechanistically, sTREM2 dose-dependently decreased the phosphorylation of GSK3β at Y216, a modification associated with enhanced kinase activity, indicating that sTREM2 mitigates tau hyperphosphorylation by suppressing GSK3β activation.

4.2 TG2 Serves as the Neuronal Receptor for sTREM2

Affinity purification and mass spectrometry identified TG2, an actin-binding protein expressed on neurons, as a major interacting partner of sTREM2. Multiplex IHC staining (facilitated by ANT BIO PTE. LTD.’s kits) confirmed the colocalization of sTREM2, TG2, and the neuronal marker MAP2 in the hippocampus of AD patients and tau P301S mice. TG2 knockdown significantly attenuated sTREM2’s binding to neurons and abolished its inhibitory effect on tau phosphorylation and GSK3β activation, demonstrating that TG2 is essential for sTREM2-mediated neuroprotection.

4.3 sTREM2 Acts Through the TG2-RhoA-ROCK-GSK3β Signaling Axis

Further mechanistic studies revealed that sTREM2 activates TG2, which in turn induces phosphorylation of RhoA at S188. This phosphorylation inactivates the RhoA-ROCK pathway, leading to suppressed GSK3β activity and subsequent reduction in tau hyperphosphorylation. This signaling cascade provides a clear molecular link between microglial sTREM2 and neuronal tau regulation.

4.4 sTREM2 Ameliorates Tau Pathology and Cognitive Deficits in Tau P301S Mice

Intrahippocampal injection of AAV-EGFP-sTREM2 in tau P301S mice significantly reduced hippocampal tau phosphorylation and GSK3β activity at 7 months of age. Electron microscopy demonstrated preserved synaptic density, and behavioral tests (Morris water maze) showed improved spatial memory. Electrophysiological recordings further confirmed enhanced long-term potentiation (LTP) of field excitatory postsynaptic potentials (fEPSCs), indicating restored synaptic function.

4.5 sTREM2-Derived Peptide Mimics Exert Therapeutic Effects In Vivo

A synthetic peptide corresponding to sTREM2 residues 77-89 (Peptide 1) was found to mimic the inhibitory effect of sTREM2 on tau phosphorylation. Intraperitoneal injection of FITC-labeled Peptide 1 confirmed its brain penetrability and interaction with neuronal TG2. Long-term treatment (4 months) of tau P301S mice with Peptide 1 significantly reduced hippocampal tau phosphorylation, suppressed GSK3β and RhoA activation, preserved synapses, and improved cognitive performance compared to mice treated with a scrambled control peptide.

5. Product Empowerment: The Critical Role of ANT BIO PTE. LTD.’s Multiplex IHC Kits

The validation of spatial colocalization between sTREM2, TG2, and neuronal markers was a cornerstone of this study, as it provided direct evidence for the proposed sTREM2-TG2 interaction in AD pathology. ANT BIO PTE. LTD.’s Absin multiplex fluorescence IHC kits delivered the high specificity, sensitivity, and multiplexing capability required for this critical validation step.

5.1 Core Products and Their Application Value

5.2 Technical Value in Neurodegenerative Disease Research

In neurodegenerative disease research, the spatial context of molecular interactions is critical for understanding pathological mechanisms. ANT BIO PTE. LTD.’s multiplex IHC kits enable researchers to visualize multiple key molecules simultaneously on a single tissue section, preserving their native spatial relationships—a capability that traditional single-marker IHC cannot match. In this study, the kits’ high sensitivity and specificity ensured clear detection of low-abundance molecules (e.g., sTREM2) in complex brain tissue samples, while their compatibility with various sample types (human AD brain sections and mouse brain sections) supported translational research from preclinical to clinical contexts. This technical empowerment was instrumental in validating the sTREM2-TG2 signaling axis, a key breakthrough in AD tauopathy research.

6. Brand Mission

As a professional supplier of life science reagents, ANT BIO PTE. LTD. is dedicated to providing high-quality, reliable products and comprehensive solutions to empower global life science research. The company's three specialized sub-brands cover the full spectrum of research needs in the life science field: Absin focuses on general reagents and kits, Starter specializes in antibodies, and UA is dedicated to recombinant proteins. Our core mission is to bridge the gap between cutting-edge scientific research and practical applications, accelerate the pace of scientific discovery, and contribute to the advancement of human health and regenerative medicine.

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8. Disclaimer

This article is AI-compiled and interpreted based on the original work in DOI: 10.1002/advs.202413562. All intellectual property (e.g., images, data) of the original publication shall belong to the journal and the research team. For any infringement, please contact us promptly and we will take immediate action.

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At ANTBIO, we are committed to advancing life science research through high-quality, reliable reagents and comprehensive solutions. Our specialized sub-brands (Absin, Starter, UA) cover a full spectrum of research needs, from general reagents and kits to antibodies and recombinant proteins. With a focus on innovation, quality, and customer-centricity, we strive to be your trusted partner in unlocking scientific mysteries and driving medical progress. Explore our product portfolio today and elevate your research to new heights.