Human Albumin Impairs Amyloid β-peptide Fibrillation Through its C-terminus
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...
| Autores: | , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:222816 |
| Acceso en línea: | https://ddd.uab.cat/record/222816 https://dx.doi.org/urn:doi:10.1016/j.csbj.2019.06.017 |
| Access Level: | acceso abierto |
| Palabra clave: | Alzheimer's disease Amyloid Albumin β-Sheet Docking AD, Alzheimer's disease APP, amyloid precursor protein Aß, Amyloid-ß peptide CD, Circular dichroism CSF, cerebrospinal fluid CTerm, albumin C-terminus Faβ, HiLyte Fluor488 labelled human Aβ 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 |
| Sumario: | 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 in vitro 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 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. |
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