Multiadducts of C₆₀ Modulate Amyloid-β Fibrillation with Dual Acetylcholinesterase Inhibition and Antioxidant Properties: In Vitro and In Silico Studies

Article type: Research Article

Authors: Martínez-Herrera, Melchor^a | Figueroa-Gerstenmaier, Susana^b | López-Camacho, Perla Y.^a | Millan-Pacheco, Cesar^c | Balderas-Altamirano, Miguel A.^b | Mendoza-Franco, Graciela^d | García-Sierra, Franciscos^d | Zavala-Ocampo, Lizeth M.^e | Basurto-Islas, Gustavo^{b; *}

Affiliations: [a] Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Cuajimalpa, Ciudad de México, México | [b] División de Ciencias e Ingenierías, Universidad de Guanajuato, Campus León, León, Gto., México | [c] Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, México | [d] Departamento de Biología Celular, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, México | [e] Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Cuajimalpa, Ciudad de México, México

Correspondence: [*] Correspondence to: Gustavo Basurto-Islas, Lomas del Bosque 103, Lomas del Campestre, 37150 León, Gto, México. E-mail: [email protected].; ORCID: 0000-0002-9401-140X

Abstract: Background:Amyloid-β (Aβ) fibrils induce cognitive impairment and neuronal loss, leading to onset of Alzheimer’s disease (AD). The inhibition of Aβ aggregation has been proposed as a therapeutic strategy for AD. Pristine C60 has shown the capacity to interact with the Aβ peptide and interfere with fibril formation but induces significant toxic effects in vitro and in vivo. Objective:To evaluate the potential of a series of C60 multiadducts to inhibit the Aβ fibrillization. Methods:A series of C60 multiadducts with four to six diethyl malonyl and their corresponding disodium-malonyl substituents were synthesized as individual isomers. Their potential on Aβ fibrillization inhibition was evaluated in vitro, in cellulo, and silico. Antioxidant activity, acetylcholinesterase inhibition capacity, and toxicity were assessed in vitro. Results:The multiadducts modulate Aβ fibrils formation without inducing cell toxicity, and that the number and polarity of the substituents play a significant role in the adducts efficacy to modulate Aβ aggregation. The molecular mechanism of fullerene-Aβ interaction and modulation was identified. Furthermore, the fullerene derivatives exhibited antioxidant capacity and reduction of acetylcholinesterase activity. Conclusion:Multiadducts of C60 are novel multi-target-directed ligand molecules that could hold considerable promise as the starting point for the development of AD therapies.

Keywords: Alzheimer’s disease, fullerenes, molecular dynamics, nanoparticles, polymerization, therapy

DOI: 10.3233/JAD-215412

Journal: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 741-759, 2022