Human Albumin Impairs Amyloid β-peptide Fibrillation Through its C-terminus: From docking Modeling to Protection Against Neurotoxicity in Alzheimer's disease.

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2019
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Abstract
Alzheimer's disease (AD) is a neurodegenerative process characterized by the accumulation of extracellular deposits of amyloid β-peptide (Aβ), which induces neuronal death. Monomeric Aβ is not toxic but tends to aggregate into β-sheets that are neurotoxic. Therefore to prevent or delay AD onset and progression one of the main therapeutic approaches would be to impair Aβ 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 Aβ impeding its aggregation. In a previous work we identified a 35-residue sequence of clusterin, a well-known protein that binds Aβ, 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-Aβ simulations was significantly lower than that of the clusterin-Aβ binding, highlighting the possibility that the CTerm retains albumin's binding properties. To validate this observation, we performed structural analysis of soluble and aggregated 1 μM Aβ incubated with 5 μM CTerm, equimolar to the albumin concentration in the CSF. Reversed-phase chromatography and electron microscopy analysis demonstrated a reduction of Aβ aggregates when the CTerm was present. Furthermore, we treated a human neuroblastoma cell line with soluble and aggregated Aβ incubated with CTerm obtaining a significant protection against Aβ-induced neurotoxicity. These and data suggest that the albumin CTerm is able to impair Aβ aggregation and to promote disassemble of Aβ aggregates protecting neurons.
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Authors Picón-Pagès, Pol;Bonet, Jaume;García-García, Javier;Garcia-Buendia, Joan;Gutierrez, Daniela;Valle, Javier;Gómez-Casuso, Carmen E S;Sidelkivska, Valeriya;Alvarez, Alejandra;Perálvarez-Marín, Alex;Suades, Albert;Fernàndez-Busquets, Xavier;Andreu, David;Vicente, Rubén;Oliva, Baldomero;Muñoz, Francisco J;
Journal computational and structural biotechnology journal
Year 2019
DOI
10.1016/j.csbj.2019.06.017
URL
Keywords
Docking amyloid alzheimer's disease albumin tfa, trifluoroacetic acid uv, ultraviolet hplc, high performance liquid chromatography ad, alzheimer's disease app, amyloid precursor protein aß, amyloid-ß peptide cd, circular dichroism csf, cerebrospinal fluid cterm, albumin c-terminus lc-ms, liquid chromatography-mass spectrometry mtt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide nmr, nuclear magnetic resonance pbs, phosphate-buffered saline pdb, protein data bank ppi, protein-protein interactions sds, sodium dodecyl sulfate tem, transmission electron microscopy faβ1–42, hilyte fluor488 labelled human aβ1–42 β-sheet

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