Small-molecule inhibitors disrupt tau-LRP1 interaction, reducing tau uptake in cellular models
Background
Tauopathies, including Alzheimer's disease, are neurodegenerative disorders characterized by the abnormal aggregation and propagation of tau protein. The cellular uptake and spread of tau aggregates are critical for disease progression, with the endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1) playing a central role in mediating this process. Despite LRP1's known involvement in tau binding and internalization, the precise biochemical characteristics of this interaction and its suitability as a therapeutic target have remained incompletely defined, representing a significant gap in developing targeted interventions.
Study Design
Researchers established a quantitative framework to investigate the tau-LRP1 interaction. They engineered and purified the LRP1 ligand-binding domain 4 (BD4), a key region for tau interaction. Multiple orthogonal assays, including fluorescence polarization, split luciferase complementation, and time-resolved FRET, were developed to measure LRP1-BD4 interactions with tau and a known peptide ligand. Leveraging these platforms, a high-throughput screen was performed to identify small-molecule inhibitors of the LRP1-BD4-tau interaction. Selected compounds were then tested in a cellular assay to assess their impact on tau uptake.
Results
Across all assay formats, consistent binding affinities for the tau-LRP1-BD4 interaction were observed in the nanomolar range. These interactions demonstrated competitive displacement by tau, receptor-associated protein (RAP), and a known peptide ligand, indicating overlapping binding interfaces. The high-throughput screening successfully identified a set of candidate small-molecule inhibitors that specifically disrupted the LRP1-BD4-tau interaction. Critically, these selected compounds were shown to reduce tau uptake in a cellular assay, effectively phenocopying the competitive inhibition achieved by tau and the peptide ligand. This work establishes the LRP1-BD4-tau interaction as a biochemically tractable and druggable interface. The integrated discovery pipeline links mechanistic characterization to functional cellular outcomes. This foundational research defines the LRP1-BD4-tau interaction as a viable target.
The identified small-molecule inhibitors significantly reduced tau uptake in cellular models, providing direct evidence of their functional efficacy.
Key Findings
- Tau-LRP1-BD4 interaction exhibits consistent binding affinities in the nanomolar range.
- Interaction is competitively displaced by tau, RAP, and peptide ligands, suggesting overlapping binding sites.
- High-throughput screening identified small-molecule inhibitors of the tau-LRP1-BD4 interaction.
- Selected small-molecule inhibitors reduced tau uptake in cellular assays.
Why It Matters
This research provides a crucial foundation for developing novel therapeutic strategies to combat tauopathies like Alzheimer's disease. By identifying small-molecule inhibitors that disrupt the tau-LRP1 interaction, a previously underexplored but critical pathway for tau propagation is now deemed druggable. This opens the door for designing compounds that could prevent the spread of toxic tau aggregates, potentially slowing or halting neurodegeneration. While still in early stages, this work establishes a clear target and a validated screening pipeline, accelerating the path toward clinical translation. Future protocols for tauopathy treatment could involve small molecules targeting LRP1 to block tau uptake and propagation.
tauopathies
alzheimer's-disease
lrp1
tau
small-molecules
neurodegeneration