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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.

Author information

1
Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, Spain.
2
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain, Spain.
3
Centre de Regulacio Genomica.
4
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic-Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, Spain.
5
Department of Neurology, Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, San Sebastian, Spain, Spain.
6
Centre for Discovery Brain Sciences and UK Dementia Research Institute, University of Edinburgh., United Kingdom of Great Britain and Northern Ireland.
7
Proteomics Unit, Center for Genomics Regulation, Barcelona Institute of Science and Technology, Spain.
8
Molecular Physiology of the Synapse Laboratory, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain., Spain.
9
Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain, Spain obelbin@santpau.cat.

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 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.

KEYWORDS:

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

PMID:
30606734
DOI:
10.1074/mcp.RA118.001290
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