{
  "abstract": "The cellular uptake and propagation of tau are central features of tauopathies, including Alzheimers disease, and are mediated by the endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1). While prior studies have implicated LRP1 in tau binding and internalization, the biochemical features of this interaction and its suitability for therapeutic targeting remain incompletely defined. Here, we establish a quantitative and scalable framework to interrogate the tau-LRP1 interaction and identify small-molecule modulators. We engineered and purified the LRP1 ligand-binding domain 4 (BD4), a key region mediating tau interaction, and developed multiple orthogonal assays, including fluorescence polarization, split luciferase complementation, and time-resolved FRET, to measure LRP1-BD4 interactions with tau and a known peptide ligand. Across assay formats, we observe consistent binding affinities in the nanomolar range and demonstrate competitive displacement by tau, receptor-associated protein (RAP), and a peptide ligand, supporting overlapping binding interfaces. Leveraging these platforms, we performed small molecule high-throughput screening and identified a set of candidate inhibitors of the LRP1-BD4-tau interaction. Selected compounds reduced tau uptake in a cellular assay, phenocopying competitive inhibition by tau and a peptide ligand. Together, these studies define the LRP1-BD4-tau interaction as a biochemically tractable and druggable interface and establish an integrated discovery pipeline linking mechanistic characterization to functional cellular outcomes. This work provides a foundation for the development of therapeutic strategies targeting LRP1-mediated tau uptake.",
  "abstract_shown": true,
  "affiliations": [
    "University of Massachusetts Amherst"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "C. Wang"
    },
    {
      "name": "C.-T. Ma"
    },
    {
      "name": "C. Crotty"
    },
    {
      "name": "F.-Y. Zeng"
    },
    {
      "name": "A. Bobkov"
    },
    {
      "name": "J. A. Covel"
    },
    {
      "name": "E. Keane Rivera"
    },
    {
      "name": "E. Sergienko"
    },
    {
      "name": "K. S. Kosik"
    },
    {
      "name": "S. H. Olson"
    },
    {
      "name": "M. R. Jackson"
    },
    {
      "affs": [
        0
      ],
      "name": "J. N. Rauch"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/32fmregcew98p.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.06.24.733881",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.06.24.733881v2.full",
  "id": "32fmregcew98p",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.06.24.733881v2",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biochemistry"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7165928705",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.06.24.733881v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-06-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/32fmregcew98p.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:32Z",
      "native_id": "10.64898/2026.06.24.733881",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.06.24.733881v2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction",
  "title_text": "High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:32Z",
  "url": "https://research.draconitic.com/paper/32fmregcew98p",
  "venue": "bioRxiv",
  "versions": []
}