Quantification of the trans-synaptic partners neurexin- neuroligin in CSF of neurodegenerative diseases by parallel reaction monitoring mass spectrometry

Background Synaptic proteins are increasingly studied as biomarkers for synaptic dysfunction and loss, which are early and central events in Alzheimer's disease (AD) and strongly correlate with the degree of cognitive decline. In this study, we specifically investigated the synaptic binding partners neurexin (NRXN) and neuroligin (Nlgn) proteins, to assess their biomarker's potential. Methods we developed a parallel reaction monitoring mass spectrometric method for the simultaneous quantification of NRXNs and Nlgns in cerebrospinal fluid (CSF) of neurodegenerative diseases, focusing on AD. Specifically, NRXN-1 alpha, NRXN-1 beta, NRXN-2 alpha, NRXN-3 alpha and Nlgn1, Nlgn2, Nlgn3 and Nlgn4 proteins were targeted. Findings The proteins were investigated in a clinical cohort including CSF from controls (n=22), mild cognitive impairment (MCI) due to AD (n=44), MCI due to other conditions (n=46), AD (n=77) and a group of non-AD dementia (n=28). No difference in levels of NRXNs and Nlgns was found between AD (both at dementia and MCI stages) or controls or the non-AD dementia group for any of the targeted proteins. NRXN and Nlgn proteins correlated strongly with each other, but only a weak correlation with the AD core biomarkers and the synaptic biomarkers neurogranin and growth-associated protein 43, was found, possibly reflecting different pathogenic processing at the synapse. Interpretation we conclude that NRXN and Nlgn proteins do not represent suitable biomarkers for synaptic pathology in AD. The panel developed here could aid in future investigations of the potential involvement of NRXNs and Nlgns in synaptic dysfunction in other disorders of the central nervous system. Copyright (C) 2021 The Author(s). Published by Elsevier B.V

Automated summary

The synaptic proteins NRXN and Nlgn are not suitable biomarkers for synaptic pathology in Alzheimer's disease, as they show weak correlation with core biomarkers and reflect different pathogenic processes at the synapse.