Abstract
A biomarker capable of detecting synapse loss, which occurs early in Alzheimer's disease (AD) pathophysiology, would greatly assist in preclinical diagnosis, when treatment would most likely be effective. The objective of this study was to characterise the cerebrospinal fluid (CSF) proteome in terms of regional brain expression, functional and physical relationship to the synapse and interaction complexes in order to identify putative CSF biomarkers that could be used in the clinic to monitor the synaptic loss associated with Alzheimer's disease. A database of the CSF proteome was constructed by performing non-targeted liquid chromatography mass spectrometry on CSF samples from 50 cognitively healthy controls and 10 AD patients. A database of the synaptic proteome was constructed by literature curation of proteins detected in synaptosome-enriched fractions or annotated with a synaptic function in online databases. Proteins that were 1) not expressed in the cortical neuropil or cortical neurons or that were highly expressed in cortical or hippocampal glia or 2) whose transcript was not enriched in the hippocampus according to data available from online databases were removed. Cross-referencing the CSF (3,005 proteins) and synaptic (1,056 proteins) proteomes produced a list of 282 proteins. This suggests that approximately 37% of the hippocampal-enriched synaptic proteome is detectable in the CSF by shotgun mass spectrometry and 12% of the CSF proteome is of hippocampal synaptic origin. Construction of an interaction map of the 282 proteins identified functional clusters of proteins that were used to select a panel of proteins for validation as CSF biomarkers for AD. By performing a detailed characterization of the CSF and synaptic proteomes and by confirming synapse expression in human brain, we have identified a panel of synaptic proteins detectable in the CSF which, if confirmed as biomarkers of synaptic loss, could be invaluable stage biomarkers for AD.
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