Abstract
BackgroundSynaptic degeneration is an early pathogenic event in Alzheimer’s disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples.ResultsWe report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer’s disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer’s disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer’s disease from controls with area under the curve of 0.901 (P < 0.0001).ConclusionsWe developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.Electronic supplementary materialThe online version of this article (doi:10.1186/1750-1326-9-53) contains supplementary material, which is available to authorized users.
Highlights
Synaptic degeneration is an early pathogenic event in Alzheimer’s disease, associated with cognitive impairment and disease progression
We found that the levels of synaptosomal-associated protein 25 (SNAP-25) were significantly lower in the Alzheimer’s disease group for the membrane-bound and the membrane-raft associated fractions (Figure 1A-B)
When affinity purifying with SMI81 instead of SP12, SNAP-25 could be quantified in all soluble fractions (Figure 1C)
Summary
Synaptic degeneration is an early pathogenic event in Alzheimer’s disease, associated with cognitive impairment and disease progression. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, these assays were not sensitive enough for individual samples. The notions that synaptic loss occurs early in Alzheimer’s disease, and that synaptic proteins at active synapses could be biomarkers indicating the degree of synaptic degeneration have prompted interest in detecting relevant synaptic proteins in human biological fluid samples. Several research groups, including our own, have detected synaptic proteins in CSF [16,17,18,19,20,21] These studies were performed on relatively large quantities of pooled CSF from multiple patients [16,17,21]. The target proteins had to be selectively purified and concentrated in several steps and the quantitative aspects of the techniques may have been sub-optimal [20]
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