Human albumin impairs amyloid ß-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease

P. Picón-Pagès, J. Bonet, J. García-García, J. García-Buendía, D. Gutiérrez, J. Valle, C. E. S. Gómez-Casuso, V. Sidelkivska, A. Álvarez, A. Perálvarez-Marín, A. Suades, X. Fernàndez-Busquets, D. Andreu, R. Vicente, B. Oliva, F.J. Muñoz

Computational and Structural Biotechnology Journal Vol. 17, pp. 963 - 971

Summary:
Alzheimer's disease (AD) is a neurodegenerative process characterized by the accumulation of extracellular deposits of amyloid ß-peptide (Aß), which induces neuronal death. Monomeric Aß is not toxic but tends to aggregate into ß-sheets that are neurotoxic. Therefore to prevent or delay AD onset and progression one of the main therapeutic approaches would be to impair Aß assembly into oligomers and fibrils and to promote disaggregation of the preformed aggregate. Albumin is the most abundant protein in the cerebrospinal fluid and it was reported to bind Aß impeding its aggregation. In a previous work we identified a 35-residue sequence of clusterin, a well-known protein that binds Aß, that is highly similar to the C-terminus (CTerm) of albumin. In this work, the docking experiments show that the average binding free energy of the CTerm-Aß1–42 simulations was significantly lower than that of the clusterin-Aß1–42 binding, highlighting the possibility that the Cterm retains albumin's binding properties. To validate this observation, we performed in vitro structural analysis of soluble and aggregated 1µM Aß1–42 incubated with 5µM Cterm, equimolar to the albumin concentration in the CSF. Reversed-phase chromatography and electron microscopy analysis demonstrated a reduction of Aß1–42 aggregates when the Cterm was present. Furthermore, we treated a human neuroblastoma cell line with soluble and aggregated Aß1–42 incubated with Cterm obtaining a significant protection against A?-induced neurotoxicity. These in silico and in vitro data suggest that the albumin Cterm is able to impair Aß aggregation and to promote disassemble of Aß aggregates protecting neurons.

Keywords: Alzheimer's disease; Amyloid; Albumin; ß-Sheet; Docking

JCR Impact Factor and WoS quartile: 6,018 - Q1 (2019); 6,000 - Q1 (2022)

DOI reference: https://doi.org/10.1016/j.csbj.2019.06.017

Published on paper: 2019.

Published on-line: June 2019.

Citation:
P. Picón-Pagès, J. Bonet, J. García-García, J. García-Buendía, D. Gutiérrez, J. Valle, C. E. S. Gómez-Casuso, V. Sidelkivska, A. Álvarez, A. Perálvarez-Marín, A. Suades, X. Fernàndez-Busquets, D. Andreu, R. Vicente, B. Oliva, F.J. Muñoz, Human albumin impairs amyloid ß-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease. Computational and Structural Biotechnology Journal. Vol. 17, pp. 963 - 971, 2019. [Online: June 2019]