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

Comput Struct Biotechnol J. 2019 Jun 26;17:963-971. doi: 10.1016/j.csbj.2019.06.017. eCollection 2019.


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-Aβ1-42 simulations was significantly lower than that of the clusterin-Aβ1-42 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 μM Aβ1-42 incubated with 5 μM CTerm, equimolar to the albumin concentration in the CSF. Reversed-phase chromatography and electron microscopy analysis demonstrated a reduction of Aβ1-42 aggregates when the CTerm was present. Furthermore, we treated a human neuroblastoma cell line with soluble and aggregated Aβ1-42 incubated with CTerm obtaining a significant protection against Aβ-induced neurotoxicity. These in silico and in vitro data suggest that the albumin CTerm is able to impair Aβ aggregation and to promote disassemble of Aβ aggregates protecting neurons.

Keywords: AD, Alzheimer's disease; APP, amyloid precursor protein; Albumin; Alzheimer's disease; Amyloid; Aß, Amyloid-ß peptide; CD, Circular dichroism; CSF, cerebrospinal fluid; CTerm, albumin C-terminus; Docking; HPLC, high performance liquid chromatography; 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; TFA, trifluoroacetic acid; UV, ultraviolet; fAβ1–42, HiLyte Fluor488 labelled human Aβ1–42; β-Sheet.