Dual-Mode Chalcone-Based Fluorescent Probe for Distinguishing Amyloid-β Oligomers and Fibrils via Microenvironment
Zhe Zhou1, Zi-Xin Chen2, Yi-Ting Zeng2
1Department of Adult Internal Medicine, Maternal and Child Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuluo Road 745, Wuhan 430074, Hubei Province, P. R. China.
Abstract:
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregates, including oligomers and fibrils, which exert distinct neurotoxic effects. Existing diagnostic probes face limitations in selectively differentiating these species, likely due to insufficient sensitivity to conformational transitions and microenvironmental variations. Here, we report a rationally engineered chalcone-based fluorescent probe, leveraging signal difference amplification and precise microenvironment matching through dual-microenvironment-responsive mechanisms via precise energy barrier modulation. By incorporating ortho-hydroxyl and para-dimethylamino groups into the chalcone scaffold, we synergistically regulated the energy barriers of twisted intramolecular charge transfer (TICT) and excited-state intramolecular proton transfer (ESIPT). This design not only enables sensitive detection of viscosity-polarity changes during Aβ aggregation but also achieves signal difference amplification to generate distinct ratiometric fluorescence signals for oligomers and fibrils, while the precise microenvironment matching of probe-group interactions ensures accurate response to Aβ species' microenvironmental traits, surpassing conventional single-response probes. Our study underscores the critical need to differentiate Aβ species and provides an advanced tool for AD pathology research.
Insights
Researchers developed a novel chalcone-based fluorescent probe to differentiate Alzheimer's disease (AD) amyloid-β (Aβ) oligomers and fibrils. This advanced tool offers precise detection of Aβ species, aiding AD pathology research.
Area of Science:
- Biochemistry
- Neuroscience
- Materials Science
Background:
- Alzheimer's disease (AD) pathology involves amyloid-β (Aβ) aggregates like oligomers and fibrils, each with distinct neurotoxic effects.
- Current diagnostic probes struggle to selectively differentiate these Aβ species due to limitations in detecting conformational and microenvironmental changes.
Purpose of the Study:
- To engineer a novel chalcone-based fluorescent probe for sensitive and selective differentiation of Aβ oligomers and fibrils.
- To develop a tool that overcomes limitations of existing probes by responding to microenvironmental variations during Aβ aggregation.
Main Methods:
- Rational design of a chalcone scaffold incorporating ortho-hydroxyl and para-dimethylamino groups to modulate energy barriers of TICT and ESIPT.
- Utilizing dual-microenvironment-responsive mechanisms for signal difference amplification and precise microenvironment matching.
- Employing ratiometric fluorescence to distinguish between Aβ oligomers and fibrils based on their unique aggregation states.
Main Results:
- The engineered probe demonstrated sensitive detection of viscosity-polarity changes associated with Aβ aggregation.
- Signal difference amplification enabled distinct ratiometric fluorescence signals for Aβ oligomers versus fibrils.
- The probe accurately responded to Aβ species' microenvironmental traits, outperforming conventional probes.
Conclusions:
- The developed chalcone-based probe provides an advanced tool for differentiating Aβ species in Alzheimer's disease research.
- This approach highlights the importance of targeting specific Aβ conformations for improved diagnostics and understanding disease mechanisms.
