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Pàgina inicial > Articles > Articles publicats > Changes in synaptic proteins precede neurodegeneration markers in preclinical Alzheimer's disease cerebrospinal fluid |
Data: | 2019 |
Resum: | 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 (Calsyntenin-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 (Calsyn-tenin-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. |
Ajuts: | Instituto de Salud Carlos III PI15-00058 Instituto de Salud Carlos III PI14-01561 Instituto de Salud Carlos III PI18-000327 Instituto de Salud Carlos III PT17-0019 Agència de Gestió d'Ajuts Universitaris i de Recerca SLT002-16-00408 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR547 |
Nota: | Altres ajuts: Additional funding came from the "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 (201426 10). |
Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Matèria: | Aged ; Alzheimer Disease ; Autopsy ; Biomarkers ; Calcium-Binding Proteins ; Early Diagnosis ; Female ; Humans ; Male ; Nerve Tissue Proteins ; Prodromal Symptoms ; Prognosis ; Proteomics ; Receptors, AMPA ; Synapses ; Syntaxin 1 ; Thy-1 Antigens |
Publicat a: | Molecular and Cellular Proteomics, Vol. 18 Núm. 3 (march 2019) , p. 546-560, ISSN 1535-9484 |
16 p, 1.7 MB |