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PXD012138

PXD012138 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleSearch for synaptic biomarkers of Alzheimer’s disease
DescriptionAs synapse degeneration is an early event in Alzheimer’s disease (AD) pathophysiology, a biofluid marker of synapse loss in living patients could be a surrogate marker of disease prognosis and therefore would be an excellent addition to the AD biomarker arsenal. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins that could be potential biomarkers of underlying synapse degeneration. The aim of this study was to identify, verify and evaluate a set of synaptic proteins as surrogate CSF markers of underlying synapse loss in AD patients. In the Discovery Stage, we combined high-throughput shotgun proteomics of the CSF with an exhaustive search of the literature and public databases for proteomic studies of the CSF and synapse. A thorough characterization of the synaptic component of the CSF identified 210 synaptic proteins that are detectable in human CSF. We selected an initial panel of 22 candidate biomarkers for evaluation. In the Verification Stage, 12 proteins were discarded due to poor detection by targeted mass spectrometry (Selected Reaction Monitoring, SRM). We confirmed the expression of the remaining 10 proteins either directly at (Calsynytenin-1, GluR2, GluR4, Neurexins 2A and 3A, Neuroligin-2, Syntaxin-1B, Thy-1 and Vamp-2), or surrounding (Tenascin-R), the human synapse using Array Tomography microscopy and biochemical fractionation methods. We quantified the synaptic panel by SRM in CSF samples from 2 independent clinical cohorts of cognitively normal controls and all clinical stages of AD (n=140). A set of the panel proteins demonstrated a non-linear profile distinct to that of existing biomarkers whereby the CSF levels were decreased at the earliest preclinical stage of AD, reflecting reduced synaptic density in these asymptomatic individuals and elevated at later symptomatic stages when neurodegeneration is widespread. In conclusion, we have identified a set of novel synapse-specific proteins that could have clinical value for assessing disease progression in individuals at-risk for AD and potentially in other neurological disorders characterized by early synapse loss.
HostingRepositoryPanoramaPublic
AnnounceDate2019-01-10
AnnouncementXMLSubmission_2019-01-10_13:12:22.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterCristina Chiva
SpeciesList scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationListCarbamidomethyl; Label:13C(6)15N(2); Label:13C(6)15N(4)
InstrumentQTRAP 5500
Dataset History
RevisionDatetimeStatusChangeLog Entry
02018-12-20 10:44:33ID requested
12019-01-10 13:12:24announced
Publication List
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, 18(3):546-560(2019) [pubmed]
Keyword List
submitter keyword: Alzheimer’s disease, cerebrospinal fluid, synapse, biomarkers, selected reaction monitoring
Contact List
Alberto Lleó
contact affiliationMemory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
contact emailAlleo@santpau.cat
lab head
Cristina Chiva
contact affiliationProteomics Unit UPF-CRG
contact emailcristina.chiva@upf.edu
dataset submitter
Full Dataset Link List
Panorama Public dataset URI