Multiple function fluorescein probe performs metal chelation, disaggregation, and modulation of aggregated Aβ and Aβ-Cu complex.
An exceptional probe comprising indole-3-carboxaldehyde fluorescein hydrazone (FI) performs multiple tasks, namely, disaggregating amyloid β (Aβ) aggregates in different biomarker environments such as cerebrospinal fluid (CSF), Aβ1-40 fibrils, β-amyloid lysozyme aggregates (LA), and U87 MG human astrocyte cells. Additionally, the probe FI binds with Cu(2+) ions selectively, disrupts the Aβ aggregates that vary from few nanometers to micrometers, and prevents their reaggregation, thereby performing disaggregation and modulation of amyloid-β in the presence as well as absence of Cu(2+) ion. The excellent selectivity of probe FI for Cu(2+) was effectively utilized to modulate the assembly of metal-induced Aβ aggregates by metal chelation with the "turn-on" fluorescence via spirolactam ring opening of FI as well as the metal-free Aβ fibrils by noncovalent interactions. These results confirm that FI has exceptional ability to perform multifaceted tasks such as metal chelation in intracellular conditions using Aβ lysozyme aggregates in cellular environments by the disruption of β-sheet rich Aβ fibrils into disaggregated forms. Subsequently, it was confirmed that FI had the ability to cross the blood-brain barrier and it also modulated the metal induced Aβ fibrils in cellular environments by "turn-on" fluorescence, which are the most vital properties of a probe or a therapeutic agent. Furthermore, the morphology changes were examined by atomic force microscopy (AFM), polarizable optical microscopy (POM), fluorescence microscopy, and dynamic light scattering (DLS) studies. These results provide very valuable clues on the Aβ (CSF Aβ fibrils, Aβ1-40 fibrils, β-amyloid lysozyme aggregates) disaggregation behavior via in vitro studies, which constitute the first insights into intracellular disaggregation of Aβ by "turn-on" method thereby influencing amyloidogenesis.
Department of Chemistry, and ‡Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati-781039, Assam, India.
B
B
Muthuraj
Department of Chemistry, and ‡Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati-781039, Assam, India.
Sourav
S
Layek
Department of Chemistry, and ‡Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati-781039, Assam, India.
S N
SN
Balaji
Department of Chemistry, and ‡Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati-781039, Assam, India.
Vishal
V
Trivedi
Department of Chemistry, and ‡Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati-781039, Assam, India.
Parameswar Krishnan
PK
Iyer
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D000067493:Dynamic Light Scattering; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009113:Muramidase / Q000378:metabolism; D061848:Optical Imaging; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D013057:Spectrum Analysis
D016229:Amyloid beta-Peptides; D002413:Cations, Divalent; D002614:Chelating Agents; D005452:Fluoresceins; D006835:Hydrazones; C000610196:indole-3-carboxaldehyde fluorescein hydrazone; D003300:Copper; D009113:Muramidase
Alzheimer’s disease; Amyloid β; aggregation; cerebrospinal fluid; fluorescein; modulator; neurodegenerative diseases; therapeutics