Changes in synaptic proteins precede neurodegeneration markers in preclinical Alzheimer's disease cerebrospinal fluid

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  • dc.contributor.author Lleó, Alberto
  • dc.contributor.author Chiva, Cristina
  • dc.contributor.author Sabidó Aguadé, Eduard, 1981-
  • dc.contributor.author Belbin, Olivia
  • dc.date.accessioned 2022-05-17T10:57:58Z
  • dc.date.available 2022-05-17T10:57:58Z
  • dc.date.issued 2019
  • dc.description.abstract A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsynytenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages (n = 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold (p < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, p = 0.04) in an independent cohort (n = 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8-fold, p < 0.04), a finding that was replicated (0.7 to 0.8-fold, p < 0.05) for 6 proteins in a third cohort (n = 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold (p < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD.
  • dc.description.sponsorship This work was supported by the following research grants: Fondos de Investigaciones Sanitarias (PI15/00058, PI14/01561, PI18/000327) from the “Fondo Europeo de Desarrollo Regional (FEDER)”, Unión Europea, “Una manera de hacer Europa” and the “Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Gobierno de España” (ISCIII). Additional funding came from the “Departament de Salut, Generalitat de Cataluña - Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2016 –2020, 2017–2019” (SLT002/16/00408, 2017SGR547), “Programa 1 Enfermedad de Alzheimer y otras demencias degenerativas” from the Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), the “Fundació Bancaria La Caixa” (4560/6393) and “La Marató” organized by the television channel, TV3 (20142610). OB is supported by the Miguel Servet program (CP13/00091) from the ISCIII and FEDER. AB is supported by the Ministerio de Economia y Competitividad, Gobierno de España and FEDER (BFU2012-34398 and BFU2015-69717-P), by the Career Integration Grant from the European Union (ref. 304111, Marie Curie Actions), by the Ramón y Cajal Fellowship (ref. RYC-2011-08391) from the Ministerio de Economia y Competitividad, Gobierno de España and by the CERCA Programme from the Generalitat de Catalunya. RN-L is supported by the research grant from the Generalitat de Catalunya (PERIS SLT/2381/2016/00099). The proteomics analyses were performed in the CRG/UPF Proteomics Unit which is part of the Proteored, PRB3 and is supported by grant PT17/0019, of the PE IDi 2013–2016, funded by ISCIII and ERDF
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Lleó A, Núñez-Llaves R, Alclea D, Chiva C, Balateu-Paños D, Colom-Cadena M et al. Changes in synaptic proteins precede neurodegeneration markers in preclinical Alzheimer's disease cerebrospinal fluid. Mol Cell Proteomics. 2019 Mar;18(3):546-560. DOI:10.1074/mcp.RA118.001290
  • dc.identifier.doi http://dx.doi.org/10.1074/mcp.RA118.001290
  • dc.identifier.issn 1535-9476
  • dc.identifier.uri http://hdl.handle.net/10230/53118
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2012-34398
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-69717-P
  • dc.rights © 2019 Albert Lleó et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. This is an Open Access article under the CC BY license
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri https://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Alzheimer, Malaltia d'
  • dc.subject.other Proteïnes
  • dc.title Changes in synaptic proteins precede neurodegeneration markers in preclinical Alzheimer's disease cerebrospinal fluid
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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