High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction
- 1University of Massachusetts Amherst
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.
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BibTeX
@misc{wang2026highthroughput,
title = {{High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction}},
author = {C. Wang and C.-T. Ma and C. Crotty and F.-Y. Zeng and A. Bobkov and J. A. Covel and E. Keane Rivera and E. Sergienko and K. S. Kosik and S. H. Olson and M. R. Jackson and J. N. Rauch},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.24.733881},
url = {https://www.biorxiv.org/content/10.64898/2026.06.24.733881v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction
AU - C. Wang
AU - C.-T. Ma
AU - C. Crotty
AU - F.-Y. Zeng
AU - A. Bobkov
AU - J. A. Covel
AU - E. Keane Rivera
AU - E. Sergienko
AU - K. S. Kosik
AU - S. H. Olson
AU - M. R. Jackson
AU - J. N. Rauch
PY - 2026
DA - 2026/06/24
PB - bioRxiv
DO - 10.64898/2026.06.24.733881
UR - https://www.biorxiv.org/content/10.64898/2026.06.24.733881v2
AB - 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.
ER -