Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease
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 o...
| Autores: | , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Universitat Pompeu Fabra |
| Repositorio: | Repositorio Digital de la UPF |
| OAI Identifier: | oai:repositori.upf.edu:10230/42277 |
| Acceso en línea: | http://hdl.handle.net/10230/42277 http://dx.doi.org/10.1016/j.csbj.2019.06.017 |
| Access Level: | acceso abierto |
| Palabra clave: | Alzheimer&apos s disease Amyloid Albumin β-Sheet Docking |
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Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's diseasePicón-Pagès, PolBonet Martínez, Jaume, 1982-García-García, Javier, 1982-Garcia-Buendia, JoanGutierrez, DanielaValle, JavierGómez-Casuso, Carmen E.S.Sidelkivska, ValeriyaAlvarez, AlejandraPerálvarez Marín, AlexSuades, AlbertFernàndez Busquets, XavierAndreu Martínez, DavidVicente García, Rubén, 1978-Oliva Miguel, BaldomeroMuñoz López, Francisco José, 1964-Alzheimer&aposs diseaseAmyloidAlbuminβ-SheetDockingAlzheimer'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.This work was supported by the Spanish Ministry of Economy and Business through grant Plan Estatal SAF2017-83372-R & SAF2014-52228-R (FEDER funds/UE) to FJM and RV; BIO2017-85329-R to BO; AGL2014-52395-C2 and AGL2017- 84097-C2-2-R to D.A.; MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”; the Chilean Government through Fondecyt 11611065 and AFB170005 to AA, and REDES 180084 to AA and FJM; ISGlobal and IBEC are members of the CERCA Programme, Generalitat de Catalunya.Elsevier201920192019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/42277http://dx.doi.org/10.1016/j.csbj.2019.06.017reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésComputational and Structural Biotechnology Journal. 2019;17:963-71info:eu-repo/grantAgreement/ES/2PE/SAF2017-83372-Rinfo:eu-repo/grantAgreement/ES/1PE/SAF2014-52228-Rinfo:eu-repo/grantAgreement/ES/1PE/BIO2017-85329-Rinfo:eu-repo/grantAgreement/ES/1PE/AGL2014-52395-C2info:eu-repo/grantAgreement/ES/2PE/AGL2017-84097-C2-2-R© 2019 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/422772026-06-12T07:21:37Z |
| dc.title.none.fl_str_mv |
Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease |
| title |
Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease |
| spellingShingle |
Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease Picón-Pagès, Pol Alzheimer&apos s disease Amyloid Albumin β-Sheet Docking |
| title_short |
Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease |
| title_full |
Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease |
| title_fullStr |
Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease |
| title_full_unstemmed |
Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease |
| title_sort |
Human albumin impairs amyloid β-peptide fibrillation through its C-terminus: from docking modeling to protection against neurotoxicity in alzheimer's disease |
| dc.creator.none.fl_str_mv |
Picón-Pagès, Pol Bonet Martínez, Jaume, 1982- García-García, Javier, 1982- 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 Martínez, David Vicente García, Rubén, 1978- Oliva Miguel, Baldomero Muñoz López, Francisco José, 1964- |
| author |
Picón-Pagès, Pol |
| author_facet |
Picón-Pagès, Pol Bonet Martínez, Jaume, 1982- García-García, Javier, 1982- 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 Martínez, David Vicente García, Rubén, 1978- Oliva Miguel, Baldomero Muñoz López, Francisco José, 1964- |
| author_role |
author |
| author2 |
Bonet Martínez, Jaume, 1982- García-García, Javier, 1982- 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 Martínez, David Vicente García, Rubén, 1978- Oliva Miguel, Baldomero Muñoz López, Francisco José, 1964- |
| author2_role |
author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Alzheimer&apos s disease Amyloid Albumin β-Sheet Docking |
| topic |
Alzheimer&apos s disease Amyloid Albumin β-Sheet Docking |
| description |
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. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019 2019 2019 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10230/42277 http://dx.doi.org/10.1016/j.csbj.2019.06.017 |
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http://hdl.handle.net/10230/42277 http://dx.doi.org/10.1016/j.csbj.2019.06.017 |
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Inglés |
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Inglés |
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Computational and Structural Biotechnology Journal. 2019;17:963-71 info:eu-repo/grantAgreement/ES/2PE/SAF2017-83372-R info:eu-repo/grantAgreement/ES/1PE/SAF2014-52228-R info:eu-repo/grantAgreement/ES/1PE/BIO2017-85329-R info:eu-repo/grantAgreement/ES/1PE/AGL2014-52395-C2 info:eu-repo/grantAgreement/ES/2PE/AGL2017-84097-C2-2-R |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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