Probing Alzheimer's pathology : exploring the next generation of FDDNP analogues for amyloid β detection

Rejc, Luka (avtor), Knez, Damijan (avtor), Molina-Aguirre, Gabriela (avtor), Espargaró, Alba (avtor), Kladnik, Jerneja (avtor), Meden, Anže (avtor), Blinc, Lana (avtor), Lozinšek, Matic (avtor), Jansen-van Vuuren, Ross D. (avtor), Rogan, Matic (avtor), Martek, Bruno Aleksander (avtor), Mlakar, Jernej (avtor), Dremelj, Ana (avtor), Petrič, Andrej (avtor), Gobec, Stanislav (avtor), Sabaté, Raimon (avtor), Bresjanac, Mara (avtor), Pinter, Balazs (avtor), Košmrlj, Janez (avtor)

Fluorescent probes are a powerful tool for imaging amyloid β (Aβ) plaques, the hallmark of Alzheimer’s disease (AD). Herein, we report the synthesis and comprehensive characterization of 21 novel probes as well as their optical properties and binding affinities to Aβ fibrils. One of these dyes, 1Ae, exhibited several improvements over FDDNP, an established biomarker for Aβ- and Tau-aggregates. First, 1Ae had large Stokes shifts (138–213 nm) in various solvents, thereby reducing self-absorption. With a high quantum yield ratio (φ(dichloromethane/methanol) = 104), 1Ae also ensures minimal background emission in aqueous environments and high sensitivity. In addition, compound 1Ae exhibited low micromolar binding affinity to Aβ fibrils in vitro (K$_d$ = 1.603 µM), while increasing fluorescence emission (106-fold) compared to emission in buffer alone. Importantly, the selective binding of 1Ae to Aβ$_{1–42}$ fibrils was confirmed by an in cellulo assay, supported by ex vivo fluorescence microscopy of 1Ae on postmortem AD brain sections, allowing unequivocal identification of Aβ plaques. The intermolecular interactions of fluorophores with Aβ were elucidated by docking studies and molecular dynamics simulations. Density functional theory calculations revealed the unique photophysics of these rod-shaped fluorophores, with a twisted intramolecular charge transfer (TICT) excited state. These results provide valuable insights into the future application of such probes as potential diagnostic tools for AD in vitro and ex vivo such as determination of Aβ$_{1–42}$ in cerebrospinal fluid or blood.

• Jezik: Angleški jezik
• Ključne besede: amyloid β, fluorophore, solvatochromism, synthesis, photophysics, Alzheimer’s disease
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FKKT - Fakulteta za kemijo in kemijsko tehnologijo ; FFA - Fakulteta za farmacijo ; MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: 19 str.
• Številčenje: Vol. 175, art. 116616
• PID: 20.500.12556/RUL-166735
• UDK: 54
• ISSN pri članku: 1950-6007
• DOI: 10.1016/j.biopha.2024.116616
• COBISS.SI-ID: 194778883
• Datum objave v RUL: 23.01.2025

Gradivo je del revije

• Naslov: Biomedicine & pharmacotherapy
• Skrajšan naslov: Biomed. pharmacother.
• Založnik: Éditions scientifiques et médicales Elsevier
• ISSN: 1950-6007
• COBISS.SI-ID: 23136261

Licence

• Licenca: CC BY-NC 4.0, Creative Commons Priznanje avtorstva-Nekomercialno 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc/4.0/deed.sl
• Opis: Licenca Creative Commons, ki prepoveduje komercialno uporabo, vendar uporabniki ne rabijo upravljati materialnih avtorskih pravic na izpeljanih delih z enako licenco.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: amiloid beta, fluorofor, solvatokromizem, sinteza, fotofizika, alzheimerjeva bolezen