{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "University of Colorado Boulder"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "D. Saeb"
    },
    {
      "name": "E. E. Lietzke"
    },
    {
      "name": "E. A. Wood"
    },
    {
      "name": "A. F. Costa"
    },
    {
      "name": "E. C. Aldrich"
    },
    {
      "name": "D. I. Fuchs"
    },
    {
      "name": "A. E. Chaghajerdi"
    },
    {
      "name": "K. D. Bruce"
    },
    {
      "affs": [
        0
      ],
      "name": "K. G. Sprenger"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/azzmfhyabsnhw.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.30.763206",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.30.763206v1.full",
  "id": "azzmfhyabsnhw",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.30.763206v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioengineering"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.30.763206v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/azzmfhyabsnhw.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T00:20:36Z",
      "native_id": "10.64898/2026.10.30.763206",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.30.763206v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioengineering",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "Investigating the therapeutic potential of soluble TREM2 interactions with Transgelin-2 in Alzheimer's disease",
  "title_text": "Investigating the therapeutic potential of soluble TREM2 interactions with Transgelin-2 in Alzheimer's disease",
  "type": "preprint",
  "updated_at": "2026-11-04T00:21:02Z",
  "url": "https://research.draconitic.com/paper/azzmfhyabsnhw",
  "venue": "bioRxiv",
  "versions": []
}