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Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid

Lleó A, Núñez-Llaves R, Alcolea D, Chiva C, Balateu-Paños D, Colom-Cadena M, Gomez-Giro G, Muñoz L, Querol-Vilaseca M, Pegueroles J, Rami L, Lladó A, Molinuevo JL, Tainta M, Clarimón J, Spires-Jones T, Blesa R, Fortea J, Martínez-Lage P, Sánchez-Valle R, Sabidó E, Bayés À, Belbin O

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
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Reference

Lleó A, Núñez-Llaves R, Alcolea D, Chiva C, Balateu-Paños D, Colom-Cadena M, Gomez-Giro G, Muñoz L, Querol-Vilaseca M, Pegueroles J, Rami L, Lladó A, Molinuevo JL, Tainta M, Clarimón J, Spires-Jones T, Blesa R, Fortea J, Martínez-Lage P, Sánchez-Valle R, Sabidó E, Bayés À, Belbin O. 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