Multiple function fluorescein probe performs metal chelation, disaggregation, and modulation of aggregated Aβ and...

Area of Science:

• Biochemistry
• Neuroscience
• Chemical Biology

Background:

• Amyloid-beta (Aβ) aggregation is central to Alzheimer's disease pathogenesis.
• Developing effective agents to disaggregate Aβ and modulate its assembly is crucial for therapeutic intervention.
• Existing probes often lack the ability to function in diverse biological environments or cross the blood-brain barrier.

Purpose of the Study:

• To develop and characterize a multifunctional probe for amyloid-beta (Aβ) aggregate disaggregation and modulation.
• To investigate the probe's efficacy in various biomarker environments and cellular models.
• To explore the probe's potential as a therapeutic agent for amyloidogenesis.

Main Methods:

• Synthesis and characterization of indole-3-carboxaldehyde fluorescein hydrazone (FI) probe.
• In vitro studies using cerebrospinal fluid (CSF), Aβ1-40 fibrils, and β-amyloid lysozyme aggregates (LA).
• Cellular studies using U87 MG human astrocyte cells and assessment of blood-brain barrier penetration.
• Morphological analysis using atomic force microscopy (AFM), polarizable optical microscopy (POM), fluorescence microscopy, and dynamic light scattering (DLS).

Main Results:

• The FI probe successfully disaggregated Aβ aggregates in diverse environments, including CSF, Aβ1-40 fibrils, LA, and within astrocyte cells.
• FI exhibited selective binding to Cu(2+) ions, enabling modulation of metal-induced Aβ aggregation via a "turn-on" fluorescence mechanism.
• The probe demonstrated the ability to prevent Aβ reaggregation and cross the blood-brain barrier, with observed intracellular effects.
• Morphological studies confirmed the disruption of β-sheet rich Aβ fibrils into disaggregated forms.

Conclusions:

• The FI probe is a versatile tool for disaggregating and modulating amyloid-beta (Aβ) aggregates in vitro and in cellular environments.
• FI's ability to chelate metal ions and its "turn-on" fluorescence mechanism offer novel strategies for targeting amyloidogenesis.
• The probe's capacity to cross the blood-brain barrier and influence intracellular Aβ aggregation highlights its potential as a therapeutic agent for neurodegenerative diseases.