Synaptic proteins as biomarkers for neurodegenerative diseases: their importance and possible uses
By Elena Camporesi
Synapses are points of connections between neurons where information is transmitted, and memories formed. The brain, especially as we get old, can be subject to different neurodegenerative diseases, leading to cognitive and/or motor disorders depending on the area and type of neurons affected. During neurodegeneration, synapses are also affected, either directly by pathological processes, or as a consequence of neuronal loss. The mechanisms leading to synaptic dysfunction and loss are not completely understood, yet, and great efforts are made trying to unravel them.
Among neurodegenerative disorders, Alzheimer’s disease (AD) is the most common cause of dementia, causing cognitive and memory disabilities. However, vascular dementia, Lewy body dementia, frontotemporal dementia and its variants, Parkinson’s disease, Huntington disease and corticobasal degeneration are also important to study in order to understand the complexity of the diverse clinical presentations of neurodegenerative disorders. The diagnosis of these diseases is challenging because more than one pathology can occur at the same time and clinical symptoms can overlap and become overt only at late stages when the disease is already advanced, too late to intervene. Except for a few genetic mutations causative of these pathologies, the vast majority of neurodegenerative disease cases are idiopathic. To support clinical diagnostics, stratification of patients for clinical trials and monitoring the effects of potentially disease-modifying drugs, biomarkers become of utmost importance and are increasingly used.
In our lab, we investigate so-called fluid biomarkers, inasmuch biological fluids as cerebrospinal fluid (CSF) and blood are used for the investigation. The general idea is that proteins that are degraded or secreted from the brain as a consequence of physiological or pathological processes, can be found in CSF and blood, and their study provides a window into what is happening in the brain.
Synaptic biomarkers represent a growing field to explore in the biomarker’s world, and with our review we tried to summarize were we are and what it is still needed. The importance of studying synaptic proteins lies in them being affected at early stages of AD and other neurodegenerative diseases, thus possibly yielding early prognostic biomarkers. Moreover, representing the site for neuronal connections and memory formation, their alteration correlates strongly with cognitive decline. Thus, using synaptic proteins should provide a tool to monitor the synapse status at early stages, possibly having a direct correlation to the cognitive performance of the patients.
Synaptic proteins can be divided in proteins primarily expressed pre-synaptically and those mainly found post-synaptically. In the first group, we mainly find proteins that participate in the release of neurotransmitters contained in the synaptic vesicles. SNAP-25, synaptotagmin-1, α-synuclein and GAP-43 are among the most studied ones. All of them, except α-synuclein, are increased in the CSF of AD patients. Neurogranin is the only postsynaptic protein extensively studied, it is important for synaptic plasticity and it has also been shown to be increased in the CSF of AD patients when compared to control individuals. This increase seems to be specific for AD and it is not observed in other neurodegenerative diseases. Multiple CSF proteomic screenings have yielded several new proteins, like neuronal pentraxins, Rab3a, 14-3-3 gamma, SV2A and synaptophysin, which are worth more investigation.
In the majority of the studies reviewed, synaptic proteins were primarily investigated in AD, due to the high prevalence of this pathology and the obvious urgency to find diagnostic and prognostic markers. However, it is also important to investigate the candidate biomarkers in other diseases, to assess their discriminative power and to better characterize what leads to the cognitive decline seen in the respective disease. Moreover, given the complexity of the brain and the multiple mechanisms involved in synaptic regulation, it is likely that one single protein will not be sufficient to depict the whole symptomatic picture, but a combination of them will be necessary. The overall aim of these studies would be to have a portfolio of synaptic biomarkers for clinical use, which can aid the diagnosis of neurodegenerative diseases, possibly have prognostic value and reflect specific changes of the synapse machinery.
Article Details
Fluid Biomarkers for Synaptic Dysfunction and Loss
Elena Camporesi, Johanna Nilsson, Ann Brinkmalm, Bruno Becker, Nicholas J Ashton, Kaj Blennow, Henrik Zetterberg
First Published August 21, 2020 Review Article
DOI: 10.1177/1177271920950319
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