Quantification of the trans-synaptic partners neurexin-neuroligin in CSF of neurodegenerative diseases by parallel reaction monitoring mass spectrometry
Elena Camporesi,
Johanna Nilsson,
Agathe Vrillon,
Emmanuel Cognat,
Claire Hourregue,
Henrik Zetterberg,
Kaj Blennow,
Bruno Becker,
Ann Brinkmalm,
Claire Paquet,
Gunnar Brinkmalm
Affiliations
Elena Camporesi
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Corresponding author.
Johanna Nilsson
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Agathe Vrillon
Université de Paris, Cognitive Neurology Center, GHU Nord APHP Hospital Lariboisière Fernand Widal, Paris, France; Université de Paris, Inserm UMR S11-44 Therapeutic Optimization in Neuropsychopharmacology, Paris, France
Emmanuel Cognat
Université de Paris, Cognitive Neurology Center, GHU Nord APHP Hospital Lariboisière Fernand Widal, Paris, France; Université de Paris, Inserm UMR S11-44 Therapeutic Optimization in Neuropsychopharmacology, Paris, France
Claire Hourregue
Université de Paris, Cognitive Neurology Center, GHU Nord APHP Hospital Lariboisière Fernand Widal, Paris, France
Henrik Zetterberg
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at UCL, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
Kaj Blennow
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Bruno Becker
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Ann Brinkmalm
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Claire Paquet
Université de Paris, Cognitive Neurology Center, GHU Nord APHP Hospital Lariboisière Fernand Widal, Paris, France; Université de Paris, Inserm UMR S11-44 Therapeutic Optimization in Neuropsychopharmacology, Paris, France
Gunnar Brinkmalm
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Summary: 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-1α, NRXN-1β, NRXN-2α, NRXN-3α 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. Funding: a full list of funding can be found under the acknowledgments section.
