Lleo_2019_Mol.Cell.Proteomics_18_546

Reference

Title : Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid - Lleo_2019_Mol.Cell.Proteomics_18_546
Author(s) : Lleo A , Nunez-Llaves R , Alcolea D , Chiva C , Balateu-Panos D , Colom-Cadena M , Gomez-Giro G , Munoz L , Querol-Vilaseca M , Pegueroles J , Rami L , Llado A , Molinuevo JL , Tainta M , Clarimon J , Spires-Jones T , Blesa R , Fortea J , Martinez-Lage P , Sanchez-Valle R , Sabido E , Bayes A , Belbin O
Ref : Mol Cell Proteomics , 18 :546 , 2019
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.

PubMedSearch : Lleo_2019_Mol.Cell.Proteomics_18_546
PubMedID: 30606734

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Lleo A, Nunez-Llaves R, Alcolea D, Chiva C, Balateu-Panos D, Colom-Cadena M, Gomez-Giro G, Munoz L, Querol-Vilaseca M, Pegueroles J, Rami L, Llado A, Molinuevo JL, Tainta M, Clarimon J, Spires-Jones T, Blesa R, Fortea J, Martinez-Lage P, Sanchez-Valle R, Sabido E, Bayes A, Belbin O (2019)
Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid
Mol Cell Proteomics 18 :546

Lleo A, Nunez-Llaves R, Alcolea D, Chiva C, Balateu-Panos D, Colom-Cadena M, Gomez-Giro G, Munoz L, Querol-Vilaseca M, Pegueroles J, Rami L, Llado A, Molinuevo JL, Tainta M, Clarimon J, Spires-Jones T, Blesa R, Fortea J, Martinez-Lage P, Sanchez-Valle R, Sabido E, Bayes A, Belbin O (2019)
Mol Cell Proteomics 18 :546