Fluid Biomarkers for Synaptic Dysfunction and Loss

Abstract

Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer’s disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and α-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.

Proteomic Analysis of Rhesus Macaque Brain Explants Treated With Borrelia burgdorferi Identifies Host GAP-43 as a Potential Factor Associated With Lyme Neuroborreliosis

“…GAP-43 is mainly expressed in the endoolfactory cortex, neocortex, and hippocampus, and is anchored on the cytoplasmic side of the presynaptic plasma membrane where it regulates synaptic plasticity and regenerative axonal growth and plays a critical role in neural development, axonal outgrowth, and stabilisation of synaptic function ( Holahan, 2017 ). GAP-43 was shown to promote neurite outgrowth during development and nervous system repair by inducing F-actin accumulation, stimulating morphogenic activity, and preventing growth cone retraction ( Zhang et al., 2018 ; Camporesi et al., 2020 ); changes in GAP-43 expression have been reported following nerve injury and in CNS diseases such as stroke, Alzheimer disease, epilepsy, and Parkinson disease ( Tönges et al., 2014 ; Nemes et al., 2017 ; Sandelius et al., 2018 ; Sandelius et al., 2019 ; Tible et al., 2020 ).…”

Proteomic Analysis of Rhesus Macaque Brain Explants Infected With Borrelia Burgdorferi Identifies Host GAP-43 As A Potential Factor Associated With Lyme Neuroborreliosis

“…GAP-43 is mainly expressed in the endoolfactory cortex, neocortex, and hippocampus, and is anchored on the cytoplasmic side of the presynaptic plasma membrane where it regulates synaptic plasticity and regenerative axonal growth and plays a critical role in neural development, axonal outgrowth, and stabilisation of synaptic function [26]. GAP-43 was shown to promote neurite outgrowth during development and nervous system repair by inducing F-actin accumulation, stimulating morphogenic activity, and preventing growth cone retraction [27,28]; changes in GAP-43 expression have been reported following nerve injury and in CNS diseases such as stroke, Alzheimer disease, epilepsy, and Parkinson disease [29][30][31][32][33].…”

Biomarkers: Our Path Towards a Cure for Alzheimer Disease

“… 20 , 50 , 51 Among the most promising markers of synaptic injury in AD are the post-synaptic protein neurogranin (Ng), 52 , 53 and the pre-synaptic proteins synaptosome–associated protein-25 (SNAP-25) 54 , 55 and synaptotagmin-1 (Syt-1), 56 although several others have been examined. 57 The abundant expression and relative neuronal specificity of these markers allow them to reliably reflect neuronal and synaptic loss, as their CSF levels correlate with damage to neuronal and synaptic structures and the release of abundant neuronal or synaptic constituents into the extracellular compartment in the setting of neurodegeneration.…”