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Mol Cell Proteomics. 2019 Mar;18(3):546-560. doi: 10.1074/mcp.RA118.001290. Epub 2019 Jan 3.

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

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From the ‡Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain;
§Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
¶Biomedical Research Institute Sant Pau (IIB Sant Pau), 08025Barcelona, Spain.
From the ‡Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.
‖Proteomics Unit, Center for Genomics Regulation, Barcelona Institute of Science and Technology, 08003 Barcelona.
**University Pompeu Fabra, 08003 Barcelona.
‡‡Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), 08015 Barcelona, Spain.
§§Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, 20009 San Sebastian, Spain.
¶¶Servicio de Neurologia, Organización Sanitaria Integrada Goierri-Alto Urola, Osakidetza, Zumárraga, España.
‖‖Centre for Discovery Brain Sciences and UK Dementia Research Institute, University of Edinburgh EH8 9JZ, UK.
***Molecular Physiology of the Synapse Laboratory, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08025, Barcelona, Spain.
‡‡‡Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain.
§Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain;


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.


Alzheimer's disease; Biomarker: Prognostic; Cerebrospinal fluid; Clinical proteomics; Selected reaction monitoring

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