A Dual-Targeted Fluorescent Probe with a Semicurcumin Structure for Imaging β-Amyloid and α-Synuclein Aggregates

Area of Science:

• Neuroscience
• Biochemistry
• Chemical Biology

Background:

• Alzheimer's disease (AD) and Parkinson's disease (PD) are prevalent neurodegenerative disorders.
• Both AD and PD are characterized by abnormal protein aggregation, specifically amyloid-β (Aβ) and α-synuclein (α-syn).
• These pathologies can co-occur in advanced stages of neurodegeneration.

Purpose of the Study:

• To develop a novel dual-target fluorescent probe for simultaneous detection of Aβ and α-syn aggregates.
• To evaluate the probe's specificity, binding affinity, and fluorescence properties.
• To assess the probe's ability to cross the blood-brain barrier (BBB) and label protein aggregates in biological samples.

Main Methods:

• Synthesis and characterization of the dual-target fluorescent probe, DiFboron-6.
• In vitro fluorescence assays to determine binding affinity (dissociation constants) and fluorescence enhancement upon binding to Aβ and α-syn aggregates.
• In vitro and ex vivo experiments, including mouse brain slice staining, to evaluate labeling efficiency and BBB penetration.

Main Results:

• DiFboron-6 demonstrated significant fluorescence enhancement (59-fold for Aβ, 49-fold for α-syn).
• The probe exhibited strong binding affinities with dissociation constants K_d(Aβ) = 12.4 nM and K_d(α-syn) = 174 nM.
• DiFboron-6 successfully labeled both Aβ and α-syn aggregates and effectively crossed the BBB.

Conclusions:

• DiFboron-6 serves as an effective dual-target detection tool for Aβ and α-syn aggregates.
• The probe's properties make it a promising candidate for diagnosing and studying neurodegenerative diseases.
• The unique structure of DiFboron-6 provides a foundation for developing advanced dual-target probes.