Abstract
BackgroundNeurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, particularly in the dendritic spine of the hippocampus and cerebral cortex. The enzymatic cleavage of Ng produces fragments that are released into cerebrospinal (CSF), which have been shown to be elevated in Alzheimer’s disease (AD) patients and predict cognitive decline. Thus, quantification of distinctive cleavage products of Ng could elucidate different features of the disease.MethodsIn this study, we developed novel ultrasensitive single molecule array (Simoa) assays for measurement of full-length neurogranin (FL-Ng) and C-terminal neurogranin (CT-Ng) fragments in CSF. The Ng Simoa assays were evaluated in CSF samples from AD patients (N = 23), mild cognitive impairment due to AD (MCI-AD) (N = 18), and from neurological controls (N = 26).ResultsThe intra-assay repeatability and inter-assay precision of the novel methods had coefficients of variation below 7% and 14%, respectively. CSF FL-Ng and CSF CT-Ng median concentrations were increased in AD patients (6.02 ng/L, P < 0.00001 and 452 ng/L, P = 0.00001, respectively) and in patients with MCI-AD (5.69 ng/L, P < 0.00001 and 566 ng/L, P < 0.00001) compared to neurological controls (0.644 ng/L and 145 ng/L). The median CSF ratio of CT-Ng/FL-Ng were decreased in AD patients (ratio = 101, P = 0.008) and in patients with MCI-AD (ratio = 115, P = 0.016) compared to neurological controls (ratio = 180). CSF of FL-Ng, CT-Ng, and ratio of CT-Ng/FL-Ng could each significantly differentiate AD patients from controls (FL-Ng, AUC = 0.907; CT-Ng, AUC = 0.913; CT-Ng/FL-Ng, AUC = 0.775) and patients with MCI-AD from controls (FL-Ng, AUC = 0.937; CT-Ng, AUC = 0.963; CT-Ng/FL-Ng, AUC = 0.785).ConclusionsAssessments of the FL-Ng and CT-Ng levels in CSF with the novel sensitive immunoassays provide a high separation of AD from controls, even in early phase of the disease. The novel Ng assays are robust and highly sensitive and may be valuable tools to study synaptic alteration in AD, as well as to monitor the effect on synaptic integrity of novel drug candidates in clinical trials.
Highlights
Neurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, in the dendritic spine of the hippocampus and cerebral cortex
Assessments of the full-length neurogranin (FL-Ng) and C-terminal neurogranin (CT-Ng) levels in cerebrospinal fluid (CSF) with the novel sensitive immunoassays provide a high separation of Alzheimer’s disease (AD) from controls, even in early phase of the disease
We evaluated if the CSF Ng levels have associations with the core CSF biomarkers, presynaptic CSF biomarkers (SNAP-25 and synaptotagmin-1) and cognition, as measured by the Mini-Mental State Examination (MMSE)
Summary
Neurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, in the dendritic spine of the hippocampus and cerebral cortex. The enzymatic cleavage of Ng produces fragments that are released into cerebrospinal (CSF), which have been shown to be elevated in Alzheimer’s disease (AD) patients and predict cognitive decline. The disease is characterized by the accumulation of extracellular amyloid-β (Aβ) plaques, intraneuronal neurofibrillary tangles (NFT), along with substantial neuronal degeneration and synaptic loss [1]. Numerous studies have consistently shown that the core AD cerebrospinal fluid (CSF) biomarkers (Aβ1–42, T-tau, and P-tau) have a high diagnostic accuracy in AD dementia and in preclinical stages of disease [2, 3]. Many synaptic proteins, including neurogranin (Ng), synaptosomal-associated protein 25 (SNAP25), and synaptotagmin-1, have been suggested to be biomarkers reflecting synaptic degeneration and synaptic loss. The synaptic functioning is the support of cognition and synaptic degeneration and synaptic loss might be much closer related to cognitive decline than the other pathological hallmarks of AD [10, 11, 15]
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