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Contactin-2, a synaptic and axonal protein, is reduced in cerebrospinal fluid and brain tissue in Alzheimer's disease.

ABSTRACT: BACKGROUND:Synaptic and axonal loss are two major mechanisms underlying Alzheimer's disease (AD) pathogenesis, and biomarkers reflecting changes in these cellular processes are needed for early diagnosis and monitoring the progression of AD. Contactin-2 is a synaptic and axonal membrane protein that interacts with proteins involved in the pathology of AD such as amyloid precursor protein (APP) and beta-secretase 1 (BACE1). We hypothesized that AD might be characterized by changes in contactin-2 levels in the cerebrospinal fluid (CSF) and brain tissue. Therefore, we aimed to investigate the levels of contactin-2 in the CSF and evaluate its relationship with disease pathology. METHODS:Contactin-2 was measured in CSF from two cohorts (selected from the Amsterdam Dementia Cohort), comprising samples from controls (cohort 1, n?=?28; cohort 2, n?=?20) and AD (cohort 1, n?=?36; cohort 2, n?=?70) using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). The relationship of contactin-2 with cognitive decline (Mini-Mental State Examination (MMSE)) and other CSF biomarkers reflecting AD pathology were analyzed. We further characterized the expression of contactin-2 in postmortem AD human brain (n?=?14) versus nondemented controls (n?=?9). RESULTS:CSF contactin-2 was approximately?1.3-fold reduced in AD patients compared with controls (p?

SUBMITTER: Chatterjee M

PROVIDER: S-EPMC5984818 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Contactin-2, a synaptic and axonal protein, is reduced in cerebrospinal fluid and brain tissue in Alzheimer's disease.

Chatterjee Madhurima M Del Campo Marta M Morrema Tjado H J THJ de Waal Matthijs M van der Flier Wiesje M WM Hoozemans Jeroen J M JJM Teunissen Charlotte E CE

Alzheimer's research & therapy 20180601 1

<h4>Background</h4>Synaptic and axonal loss are two major mechanisms underlying Alzheimer's disease (AD) pathogenesis, and biomarkers reflecting changes in these cellular processes are needed for early diagnosis and monitoring the progression of AD. Contactin-2 is a synaptic and axonal membrane protein that interacts with proteins involved in the pathology of AD such as amyloid precursor protein (APP) and beta-secretase 1 (BACE1). We hypothesized that AD might be characterized by changes in cont ...[more]

PMID: 29859129

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Project description: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.

Dataset Information

Contactin-2, a synaptic and axonal protein, is reduced in cerebrospinal fluid and brain tissue in Alzheimer's disease.

Publications

Contactin-2, a synaptic and axonal protein, is reduced in cerebrospinal fluid and brain tissue in Alzheimer's disease.

Similar Datasets

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