Neuroligin-1 in brain and CSF of neurodegenerative disorders: investigation for synaptic biomarkers

Elena Camporesi,Tammaryn Lashley,Kaj Blennow,Johan Gobom,Henrik Zetterberg,Oskar Hansson,Juan Lantero-Rodriguez,Bruno Becker

doi:10.1186/s40478-021-01119-4

Abstract

Synaptic pathology is a central event in Alzheimer’s disease (AD) and other neurodegenerative conditions, and investigation of synaptic proteins can provide valuable tools to follow synaptic dysfunction and loss in these diseases. Neuroligin-1 (Nlgn1) is a postsynaptic cell adhesion protein, important for synapse stabilization and formation. Nlgn1 has been connected to cognitive disorders, and specifically to AD, as target of the synaptotoxic effect of amyloid-β (Aβ) oligomers and Aβ fibrils. To address changes in Nlgn1 expression in human brain, brain regions in different neurological disorders were examined by Western blot and mass spectrometry. Brain specimens from AD (n = 23), progressive supranuclear palsy (PSP, n = 11), corticobasal degeneration (CBD, n = 10), and Pick’s disease (PiD, n = 9) were included. Additionally, cerebrospinal fluid (CSF) samples of AD patients (n = 43) and non-demented controls (n = 42) were analysed. We found decreased levels of Nlgn1 in temporal and parietal cortex (~ 50–60% reductions) in AD brains compared with controls. In frontal grey matter the reduction was not seen for AD patients; however, in the same region, marked reduction was found for PiD (~ 77%), CBD (~ 66%) and to a lesser extent for PSP (~ 43%), which could clearly separate these tauopathies from controls. The Nlgn1 level was reduced in CSF from AD patients compared to controls, but with considerable overlap. The dramatic reduction of Nlgn1 seen in the brain extracts of tauopathies warrants further investigation regarding the potential use of Nlgn1 as a biomarker for these neurodegenerative diseases.

Highlights

Synapses are the neuron connecting units, essential for their communication, formed by a presynaptic compartment containing vesicles for storage and release of neurotransmitters, and a postsynaptic compartment containing receptors to capture and elaborate the signal and eventually, transmit it further [1]
To test whether western blots could be used to detect Neu‐ roligin-1 (Nlgn1) shedding in Alzheimers disease (AD), Tris-buffered saline (TBS)-soluble brain extracts were used and analysed with two different antibodies targeting the extracellular domain of the protein
In this study, we addressed in two sets of experiments (Study 1–2) the question whether Nlgn1 protein levels are changed in TBS extracts from various brain regions from patients with neurodegenerative diseases

Summary

Introduction

Synapses are the neuron connecting units, essential for their communication, formed by a presynaptic compartment containing vesicles for storage and release of neurotransmitters, and a postsynaptic compartment containing receptors to capture and elaborate the signal and eventually, transmit it further [1]. Altered synaptic functions and loss of synapses underlie the cognitive impairment seen in Alzheimers disease (AD) [2–6], Camporesi et al acta neuropathol commun (2021) 9:19 an AD profile in living humans. These CSF biomarkers are part of the research diagnostic criteria for AD [17], they have no diagnostic value for other neurodegenerative disorder. Synaptic dysfunction appears to be an early event in AD [2, 18] and other neurodegenerative diseases, correlating with clinical symptoms, synaptic proteins can be candidates for early biomarkers. Many synaptic proteins have been investigated [19], more investigations are needed to be able to use these biomarkers as part of the diagnostic work-up of neurodegenerative diseases in the clinic. Different synaptic proteins can reflect different pathological responses, the investigation of many synaptic proteins can improve the understanding of the pathological processes affecting synapses during neurodegenerative diseases

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