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Nanopore analysis of β-amyloid peptide aggregation transition induced by small molecules
Hai-Yan Wang1, Yi-Lun Ying, Yang Li
1Shanghai Key Laboratory of Functional Materials Chemistry & Department of Chemistry, East China University of Science and Technology, Shanghai 200237, China.
Abstract:
β-Amyloid 42 (Aβ42) is the predominant form of the amyloid peptide, which is found in the plaques of the brains of Alzheimer's (AD) patients and is one of the most abundant components in amyloid aggregates. Information of the Aβ42 aggregation states is essential for developing an understanding of the pathologic process of amyloidoses. Here, we used α-hemolysin (α-HL) pores to probe the different aggregation transition of Aβ42 in the presence of β-cyclodextrin (β-CD), a promoter of Aβ42 aggregations, and in the presence of Congo red (CR), an inhibitor of aggregations. Analyzing the characteristic transit duration times and blockade currents showed that β-CD and CR have opposite effects on the aggregation of Aβ42. Translocation events of the monomeric Aβ42 peptide were significantly lower in amplitude currents than protofilaments, and protofilaments were captured in the α-HL nanopore with a longer duration time. CR binds to Aβ42 and its peptide fibrils by reducing the aggregated fibrils formation. In this process it is assumed CR interferes with intermolecular hydrogen bonding present in the aggregates. In contrast to CR, β-CD promotes the aggregation of Aβ42. These differences can readily be analyzed by monitoring the corresponding characteristic blockade events using a biological α-HL nanopore.
Insights
This study used alpha-hemolysin (α-HL) nanopores to analyze beta-amyloid 42 (Aβ42) aggregation. Results show beta-cyclodextrin (β-CD) promotes Aβ42 aggregation, while Congo red (CR) inhibits it.
Area of Science:
- Biophysics
- Neuroscience
- Biochemistry
Background:
- Beta-amyloid 42 (Aβ42) aggregation is central to Alzheimer's disease (AD) pathology.
- Understanding Aβ42 aggregation states is crucial for developing effective treatments.
- Amyloid plaques in AD brains are primarily composed of Aβ42.
Purpose of the Study:
- To investigate the distinct aggregation transitions of Aβ42.
- To analyze the effects of aggregation promoter β-cyclodextrin (β-CD) and inhibitor Congo red (CR) on Aβ42.
- To utilize α-hemolysin (α-HL) nanopores for probing Aβ42 aggregation dynamics.
Main Methods:
- Employing α-hemolysin (α-HL) biological nanopores as a sensing platform.
- Monitoring translocation events of Aβ42 peptides through the α-HL pore.
- Analyzing characteristic transit duration times and blockade currents of aggregated Aβ42 species.
Main Results:
- β-CD and CR exhibit opposing effects on Aβ42 aggregation.
- Monomeric Aβ42 translocation events showed lower current amplitudes than protofilaments.
- Protofilaments were captured in the α-HL nanopore for longer durations compared to monomers.
- CR binding to Aβ42 reduced fibril formation, potentially by interfering with hydrogen bonds.
- β-CD was observed to promote Aβ42 aggregation.
Conclusions:
- α-HL nanopores can effectively differentiate between various Aβ42 aggregation states.
- β-CD and CR modulate Aβ42 aggregation in distinct ways, offering potential therapeutic targets.
- Monitoring blockade events in α-HL nanopores provides a sensitive method for studying amyloid aggregation.
