Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28k

Amyloid β1–42 (Aβ(1–42)) oligomers have been linked to the pathogenesis of Alzheimer’s disease (AD). Intracellular calcium (Ca2+) homeostasis dysregulation with subsequent alterations of neuronal excitability has been proposed to mediate Aβ neurotoxicity in AD. The Ca2+ binding proteins calmodulin (...

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Autores: Salazar, Jairo, Poejo, Joana, Mata, Ana M., Samhan-Arias, Alejandro K., Gutiérrez-Merino, Carlos
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/283739
Acceso en línea:http://hdl.handle.net/10261/283739
Access Level:acceso abierto
Palabra clave:Amyloid β
calmodulin
Calbindin-D28k
Antagonist peptide
Alzheimer’s disease
Fluorescence
docking
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spelling Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28kSalazar, JairoPoejo, JoanaMata, Ana M.Samhan-Arias, Alejandro K.Gutiérrez-Merino, CarlosAmyloid βcalmodulinCalbindin-D28kAntagonist peptideAlzheimer’s diseaseFluorescencedockingAmyloid β1–42 (Aβ(1–42)) oligomers have been linked to the pathogenesis of Alzheimer’s disease (AD). Intracellular calcium (Ca2+) homeostasis dysregulation with subsequent alterations of neuronal excitability has been proposed to mediate Aβ neurotoxicity in AD. The Ca2+ binding proteins calmodulin (CaM) and calbindin-D28k, whose expression levels are lowered in human AD brains, have relevant roles in neuronal survival and activity. In previous works, we have shown that CaM has a high affinity for Aβ(1–42) oligomers and extensively binds internalized Aβ(1–42) in neurons. In this work, we have designed a hydrophobic peptide of 10 amino acid residues: VFAFAMAFML (amidated-C-terminus amino acid) mimicking the interacting domain of CaM with Aβ (1–42), using a combined strategy based on the experimental results obtained for Aβ(1–42) binding to CaM and in silico docking analysis. The increase in the fluorescence intensity of Aβ(1–42) HiLyteTM-Fluor555 has been used to monitor the kinetics of complex formation with CaM and with calbindin-D28k. The complexation between nanomolar concentrations of Aβ(1–42) and calbindin-D28k is also a novel finding reported in this work. We found that the synthetic peptide VFAFAMAFML (amidated-C-terminus amino acid) is a potent inhibitor of the formation of Aβ(1–42):CaM and of Aβ(1–42):calbindin-D28k complexes.This work has been supported by Grant BFU2017-85723-P of the Spanish Ministerio de Ciencia, Innovación y Universidades (Spanish National R&D program) to Ana M. Mata and Carlos Gutierrez-Merino, and was co-financed by the European Funds for Structural Development (FEDER).Multidisciplinary Digital Publishing InstituteMinisterio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/283739reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//BFU2017-85723-Phttp://dx.doi.org/10.3390/ijms23042289Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2837392026-05-22T06:33:51Z
dc.title.none.fl_str_mv Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28k
title Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28k
spellingShingle Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28k
Salazar, Jairo
Amyloid β
calmodulin
Calbindin-D28k
Antagonist peptide
Alzheimer’s disease
Fluorescence
docking
title_short Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28k
title_full Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28k
title_fullStr Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28k
title_full_unstemmed Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28k
title_sort Design and experimental evaluation of a peptide antagonist against amyloid β(1–42) interactions with calmodulin and calbindin-D28k
dc.creator.none.fl_str_mv Salazar, Jairo
Poejo, Joana
Mata, Ana M.
Samhan-Arias, Alejandro K.
Gutiérrez-Merino, Carlos
author Salazar, Jairo
author_facet Salazar, Jairo
Poejo, Joana
Mata, Ana M.
Samhan-Arias, Alejandro K.
Gutiérrez-Merino, Carlos
author_role author
author2 Poejo, Joana
Mata, Ana M.
Samhan-Arias, Alejandro K.
Gutiérrez-Merino, Carlos
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Amyloid β
calmodulin
Calbindin-D28k
Antagonist peptide
Alzheimer’s disease
Fluorescence
docking
topic Amyloid β
calmodulin
Calbindin-D28k
Antagonist peptide
Alzheimer’s disease
Fluorescence
docking
description Amyloid β1–42 (Aβ(1–42)) oligomers have been linked to the pathogenesis of Alzheimer’s disease (AD). Intracellular calcium (Ca2+) homeostasis dysregulation with subsequent alterations of neuronal excitability has been proposed to mediate Aβ neurotoxicity in AD. The Ca2+ binding proteins calmodulin (CaM) and calbindin-D28k, whose expression levels are lowered in human AD brains, have relevant roles in neuronal survival and activity. In previous works, we have shown that CaM has a high affinity for Aβ(1–42) oligomers and extensively binds internalized Aβ(1–42) in neurons. In this work, we have designed a hydrophobic peptide of 10 amino acid residues: VFAFAMAFML (amidated-C-terminus amino acid) mimicking the interacting domain of CaM with Aβ (1–42), using a combined strategy based on the experimental results obtained for Aβ(1–42) binding to CaM and in silico docking analysis. The increase in the fluorescence intensity of Aβ(1–42) HiLyteTM-Fluor555 has been used to monitor the kinetics of complex formation with CaM and with calbindin-D28k. The complexation between nanomolar concentrations of Aβ(1–42) and calbindin-D28k is also a novel finding reported in this work. We found that the synthetic peptide VFAFAMAFML (amidated-C-terminus amino acid) is a potent inhibitor of the formation of Aβ(1–42):CaM and of Aβ(1–42):calbindin-D28k complexes.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/283739
url http://hdl.handle.net/10261/283739
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//BFU2017-85723-P
http://dx.doi.org/10.3390/ijms23042289
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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