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Updated: Apr 12, 2026
Detecting Amyloid-β Accumulation via Immunofluorescent Staining in a Mouse Model of Alzheimer's Disease
Published on: April 19, 2021
Identification of a Compound That Disrupts Binding of Amyloid-β to the Prion Protein Using a Novel Fluorescence-based
Emmanuel Risse1, Andrew J Nicoll1, William A Taylor1
1From the Medical Research Council (MRC) Prion Unit and Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London WC1N 3BG, United Kingdom.
Abstract:
The prion protein (PrP) has been implicated both in prion diseases such as Creutzfeldt-Jakob disease, where its monomeric cellular isoform (PrP(C)) is recruited into pathogenic self-propagating polymers of misfolded protein, and in Alzheimer disease, where PrP(C) may act as a receptor for synaptotoxic oligomeric forms of amyloid-β (Aβ). There has been considerable interest in identification of compounds that bind to PrP(C), stabilizing its native fold and thereby acting as pharmacological chaperones to block prion propagation and pathogenesis. However, compounds binding PrP(C) could also inhibit the binding of toxic Aβ species and may have a role in treating Alzheimer disease, a highly prevalent dementia for which there are currently no disease-modifying treatments. However, the absence of a unitary, readily measurable, physiological function of PrP makes screening for ligands challenging, and the highly heterogeneous nature of Aβ oligomer preparations makes conventional competition binding assays difficult to interpret. We have therefore developed a high-throughput screen that utilizes site-specifically fluorescently labeled protein to identify compounds that bind to PrP and inhibit both Aβ binding and prion propagation. Following a screen of 1,200 approved drugs, we identified Chicago Sky Blue 6B as the first small molecule PrP ligand capable of inhibiting Aβ binding, demonstrating the feasibility of development of drugs to block this interaction. The interaction of Chicago Sky Blue 6B was characterized by isothermal titration calorimetry, and its ability to inhibit Aβ binding and reduce prion levels was established in cell-based assays.
Insights
Researchers identified Chicago Sky Blue 6B, a novel small molecule, that binds to the prion protein (PrP). This compound inhibits amyloid-beta (Aβ) binding and reduces prion propagation, offering potential therapeutic strategies for neurodegenerative diseases like Alzheimer's.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- The prion protein (PrP) is linked to prion diseases and Alzheimer disease (AD), where it may mediate amyloid-beta (Aβ) toxicity.
- Developing pharmacological chaperones that bind and stabilize PrP(C) is a therapeutic strategy for prion diseases and potentially AD.
- Screening for PrP ligands is challenging due to the lack of a clear physiological function for PrP and the heterogeneity of Aβ oligomers.
Purpose of the Study:
- To develop a high-throughput screening method to identify compounds binding to PrP and inhibiting Aβ binding and prion propagation.
- To discover novel small molecules that can act as PrP ligands and modulate PrP interactions relevant to neurodegenerative diseases.
Main Methods:
- Developed a high-throughput screen using site-specifically fluorescently labeled PrP.
- Screened 1,200 approved drugs for compounds that bind PrP and inhibit Aβ binding.
- Characterized the interaction of identified compounds using isothermal titration calorimetry and cell-based assays.
Main Results:
- Identified Chicago Sky Blue 6B as the first small molecule PrP ligand that inhibits Aβ binding.
- Demonstrated that Chicago Sky Blue 6B can reduce prion levels in cell-based assays.
- Confirmed the feasibility of developing drugs that target PrP to block Aβ binding and prion propagation.
Conclusions:
- Chicago Sky Blue 6B is a promising lead compound for developing therapeutics against prion diseases and Alzheimer disease.
- The developed high-throughput screening method is effective for identifying PrP-targeting compounds.
- Targeting PrP interactions offers a viable strategy for treating neurodegenerative conditions involving protein misfolding and aggregation.
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