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Mol Cell Proteomics. 2019 Jan 3. pii: mcp.RA118.001290. doi: 10.1074/mcp.RA118.001290. [Epub ahead of print]

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

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Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, Spain.
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain, Spain.
Centre de Regulacio Genomica.
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, Spain.
Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain, Spain.
Centre for Discovery Brain Sciences and UK Dementia Research Institute, University of Edinburgh., United Kingdom of Great Britain and Northern Ireland.
Proteomics Unit, Center for Genomics Regulation, Barcelona Institute of Science and Technology, Spain.
Molecular Physiology of the Synapse Laboratory, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain., Spain.
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain, 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 due to 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 to 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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