Investigating the therapeutic potential of soluble TREM2 interactions with Transgelin-2 in Alzheimer's disease
- 1University of Colorado Boulder
Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is a regulator of microglial function in Alzheimer's disease (AD), and its soluble ectodomain (sTREM2) has emerged as a potential neuroprotective factor. Recent work shows that sTREM2 exerts protective effects through direct interaction with neuronal transgelin-2 (TG2) and modulates downstream tau pathology, yet the molecular basis of this interaction remains unknown. Here, we use all-atom molecular dynamics simulations to define the structural mechanisms of sTREM2-TG2 binding. We identify an electrostatically driven interface centered on the TG2 calponin homology domain. This surface is engaged by a binding motif on sTREM2 in which charged anchoring residues are flanked by hydrophobic contacts. We further show that the AD-risk TREM2R47H variant maintains a more open, solvent-exposed CDR2 loop that redistributes interfacial contacts while preserving overall binding affinity, offering a structural explanation for reports that R47H does not exacerbate tau pathology in tauopathy models. Leveraging these insights, we design optimized sTREM2-derived peptides that outperform a previously reported therapeutic peptide in binding persistence, energetics, and recapitulation of native TG2 contacts, supporting engagement at the epitope through which sTREM2 suppresses tau phosphorylation. Taken together, our results define a mechanistic framework for the sTREM2-TG2 axis in AD and establish a structure-guided strategy for developing peptide modulators of this interaction.
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BibTeX
@misc{saeb2026investigating,
title = {{Investigating the therapeutic potential of soluble TREM2 interactions with Transgelin-2 in Alzheimer's disease}},
author = {D. Saeb and E. E. Lietzke and E. A. Wood and A. F. Costa and E. C. Aldrich and D. I. Fuchs and A. E. Chaghajerdi and K. D. Bruce and K. G. Sprenger},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.763206},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.763206v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Investigating the therapeutic potential of soluble TREM2 interactions with Transgelin-2 in Alzheimer's disease
AU - D. Saeb
AU - E. E. Lietzke
AU - E. A. Wood
AU - A. F. Costa
AU - E. C. Aldrich
AU - D. I. Fuchs
AU - A. E. Chaghajerdi
AU - K. D. Bruce
AU - K. G. Sprenger
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.763206
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.763206v1
AB - Triggering receptor expressed on myeloid cells 2 (TREM2) is a regulator of microglial function in Alzheimer's disease (AD), and its soluble ectodomain (sTREM2) has emerged as a potential neuroprotective factor. Recent work shows that sTREM2 exerts protective effects through direct interaction with neuronal transgelin-2 (TG2) and modulates downstream tau pathology, yet the molecular basis of this interaction remains unknown. Here, we use all-atom molecular dynamics simulations to define the structural mechanisms of sTREM2-TG2 binding. We identify an electrostatically driven interface centered on the TG2 calponin homology domain. This surface is engaged by a binding motif on sTREM2 in which charged anchoring residues are flanked by hydrophobic contacts. We further show that the AD-risk TREM2R47H variant maintains a more open, solvent-exposed CDR2 loop that redistributes interfacial contacts while preserving overall binding affinity, offering a structural explanation for reports that R47H does not exacerbate tau pathology in tauopathy models. Leveraging these insights, we design optimized sTREM2-derived peptides that outperform a previously reported therapeutic peptide in binding persistence, energetics, and recapitulation of native TG2 contacts, supporting engagement at the epitope through which sTREM2 suppresses tau phosphorylation. Taken together, our results define a mechanistic framework for the sTREM2-TG2 axis in AD and establish a structure-guided strategy for developing peptide modulators of this interaction.
ER -