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High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction.

Caiqin Wang^1,2, Chen-Ting Ma³, Camryn Crotty^1,2

¹Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Amherst, MA, USA.

Biorxiv : the Preprint Server for Biology

|July 3, 2026

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Researchers identified a druggable target for Alzheimer's disease therapies by characterizing the interaction between tau protein and the LRP1 receptor. Small molecules were found to inhibit this interaction, reducing tau uptake in cells.

Area of Science:

Neuroscience
Biochemistry
Pharmacology

Background:

Tauopathies, including Alzheimer's disease, involve cellular tau propagation mediated by the low-density lipoprotein receptor-related protein 1 (LRP1).
The precise biochemical mechanisms of tau binding and internalization via LRP1 and its therapeutic potential are not fully understood.

Purpose of the Study:

To develop a quantitative framework for studying the tau-LRP1 interaction.
To identify small molecules that can modulate this interaction for therapeutic purposes.

Main Methods:

Engineered and purified the LRP1 ligand-binding domain 4 (BD4).
Utilized fluorescence polarization, split luciferase complementation, and time-resolved FRET assays to measure binding affinities.
Performed high-throughput screening for small-molecule inhibitors.

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Last Updated: Jul 4, 2026

In Vitro Assay for Studying the Aggregation of Tau Protein and Drug Screening

In Vitro Assay for Studying the Aggregation of Tau Protein and Drug Screening

Published on: November 20, 2018

In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein

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Published on: January 2, 2015

Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b

Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b

Published on: November 11, 2016

Main Results:

Established nanomolar binding affinities between LRP1-BD4 and tau, confirmed by competitive displacement assays.
Identified candidate small molecules inhibiting the LRP1-BD4-tau interaction.
Demonstrated that selected compounds reduce cellular tau uptake.

Conclusions:

The LRP1-BD4-tau interaction is biochemically tractable and a viable therapeutic target.
An integrated discovery pipeline linking mechanistic studies to cellular outcomes was established.
This work lays the groundwork for developing LRP1-targeted therapies for tauopathies.