Abstract

Alzheimer's disease (AD) is a neurodegenerative process characterized by the accumulation of extracellular deposits of amyloid beta-peptide (A beta), which induces neuronal death. Monomeric A beta is not toxic but tends to aggregate into beta-sheets that are neurotoxic. Therefore to prevent or delay AD onset and progression one of the main therapeutic approaches would be to impair A beta 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 A beta impeding its aggregation. In a previous work we identified a 35-residue sequence of clusterin, a well-known protein that binds A beta, 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-A beta(1-42) simulations was significantly lower than that of the clusterin-A beta(1-42) 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 1 mu M A beta(1-42) incubated with 5 mu M CTerm, equimolar to the albumin concentration in the CSF. Reversed-phase chromatography and electron microscopy analysis demonstrated a reduction of A beta(1-42) aggregates when the CTerm was present. Furthermore, we treated a human neuroblastoma cell line with soluble and aggregated A beta(1-42) incubated with (Term obtaining a significant protection against A beta-induced neurotoxicity. These in silico and in vitro data suggest that the albumin (Term is able to impair A beta aggregation and to promote disassemble of A beta aggregates protecting neurons. (C) 2019 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.