Fluid Biomarkers for Synaptic Dysfunction and Loss

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.

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Neurogranin and Neuronal Pentraxin Receptor as Synaptic Dysfunction Biomarkers in Alzheimer’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm10194575 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4575

Author(s):

Maciej Dulewicz ◽

Agnieszka Kulczyńska-Przybik ◽

Agnieszka Słowik ◽

Renata Borawska ◽

Barbara Mroczko

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Synaptic Proteins ◽

Synaptic Dysfunction ◽

Enzyme Linked Immunosorbent Assay ◽

Synaptic Loss ◽

Neuronal Pentraxin ◽

The Relationship ◽

Xmap Technology

Synaptic loss and dysfunction are one of the earliest signs of neurodegeneration associated with cognitive decline in Alzheimer’s disease (AD). It seems that by assessing proteins related to synapses, one may reflect their dysfunction and improve the understanding of neurobiological processes in the early stage of the disease. To our best knowledge, this is the first study that analyzes the CSF concentrations of two synaptic proteins together, such as neurogranin (Ng) and neuronal pentraxins receptor (NPTXR) in relation to neurochemical dementia biomarkers in Alzheimer’s disease. Methods: Ng, NPTXR and classical AD biomarkers concentrations were measured in the CSF of patients with AD and non-demented controls (CTRL) using an enzyme-linked immunosorbent assay (ELISA) and Luminex xMAP technology. Results: The CSF level of Ng was significantly higher, whereas the NPTXR was significantly lower in the AD patients than in cognitively healthy controls. As a first, we calculated the NPTXR/Ng ratio as an indicator of synaptic disturbance. The patients with AD presented a significantly decreased NPTXR/Ng ratio. The correlation was observed between both proteins in the AD and the whole study group. Furthermore, the relationship between the Ng level and pTau181 was found in the AD group of patients. Conclusions: The Ng and NPTXR concentrations in CSF are promising synaptic dysfunction biomarkers reflecting pathological changes in AD.

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

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01119-4 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Elena Camporesi ◽

Tammaryn Lashley ◽

Johan Gobom ◽

Juan Lantero-Rodriguez ◽

Oskar Hansson ◽

...

Keyword(s):

Amyloid Β ◽

Cognitive Disorders ◽

Corticobasal Degeneration ◽

Brain Regions ◽

Synaptic Proteins ◽

Aβ Oligomers ◽

Adhesion Protein ◽

Synaptic Pathology ◽

Brain Extracts ◽

Aβ Fibrils

AbstractSynaptic 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.

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Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration

Journal of Neural Transmission ◽

10.1007/s00702-021-02411-2 ◽

2021 ◽

Author(s):

Nerea Gómez de San José ◽

Federico Massa ◽

Steffen Halbgebauer ◽

Patrick Oeckl ◽

Petra Steinacker ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Expression Patterns ◽

Disease Status ◽

Synaptic Function ◽

Synaptic Activity ◽

Diagnostic Tools ◽

Synaptic Dysfunction ◽

Csf Biomarkers ◽

Prognostic Information ◽

Reliable Quantification

AbstractThe diagnosis of neurodegenerative disorders is often challenging due to the lack of diagnostic tools, comorbidities and shared pathological manifestations. Synaptic dysfunction is an early pathological event in many neurodegenerative disorders, but the underpinning mechanisms are still poorly characterised. Reliable quantification of synaptic damage is crucial to understand the pathophysiology of neurodegeneration, to track disease status and to obtain prognostic information. Neuronal pentraxins (NPTXs) are extracellular scaffolding proteins emerging as potential biomarkers of synaptic dysfunction in neurodegeneration. They are a family of proteins involved in homeostatic synaptic plasticity by recruiting post-synaptic receptors into synapses. Recent research investigates the dynamic changes of NPTXs in the cerebrospinal fluid (CSF) as an expression of synaptic damage, possibly related to cognitive impairment. In this review, we summarise the available data on NPTXs structure and expression patterns as well as on their contribution in synaptic function and plasticity and other less well-characterised roles. Moreover, we propose a mechanism for their involvement in synaptic damage and neurodegeneration and assess their potential as CSF biomarkers for neurodegenerative diseases.

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Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽

10.3390/cells10113261 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3261

Author(s):

Xiao Liu ◽

Qian Zhou ◽

Jia-He Zhang ◽

Xiaoying Wang ◽

Xiumei Gao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Disease Model ◽

Amyloid Β ◽

Brain Lesions ◽

Synaptic Dysfunction ◽

Synaptic Loss ◽

And Function ◽

The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

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miR-132 regulates the expression of synaptic proteins in APP/PS1 transgenic mice through C1q

European Journal of Histochemistry ◽

10.4081/ejh.2019.3008 ◽

2019 ◽

Vol 63 (2) ◽

Cited By ~ 5

Author(s):

Nan Xu ◽

Ang-Di Li ◽

Li-Li Ji ◽

Yao Ye ◽

Zhen-Yu Wang ◽

...

Keyword(s):

Transgenic Mice ◽

Cognitive Abilities ◽

Early Stage ◽

Amyloid Β ◽

In Silico Analysis ◽

Synaptic Proteins ◽

Downstream Target ◽

Key Factor ◽

The Central Nervous System ◽

Synapse Degeneration

Cognitive impairment in Alzheimer’s disease (AD) is usually accompanied by synaptic loss in both the hippocampus and neocortex. In the early stage of AD, amyloid β-induced synapse changes is the main reason, while in the later stage, the accumulation of Tau protein promotes synapse degeneration as the key factor leading to dementia. MicroRNA (miRNA) is closely related to the expression changes of many AD-related genes. One of the most abundant brain-enriched miRNAs is miR-132, which has been shown to regulate both neuron morphogenesis and plasticity. It has been reported that miR-132 is significantly reduced in the brains of Alzheimer’s patients. Genetic deletion of miR-132 in mice promotes Aβ deposition, leading to impaired memory and enhanced Tau pathology, but how the miRNA-mediated gene expression dysregulation contributes to AD pathology remains unclear. Here we found the possible downstream target of miR-132 by in silico analysis, namely C1q. C1q is the primary protein of classical complement cascade, which is highly expressed in the synaptic regions of the central nervous system in Alzheimer’s patients. However, it is not clear whether miR-132 plays a role in AD through regulating C1q. To address this question, the APP/PS1 transgenic mice were transfected with miR-132 and given C1 inhibitors. Behavior tests were conducted to assess memory and cognitive abilities seven days after administration. In addition, we analyzed the expression of PSD95, Synapsin-1 and phosphorylated (p)-Synapsin. We found that the expression levels of the synaptic proteins treated with miR-132 or C1INH were significantly increased compared with the AD group. Further RT-qPCR result suggested that miR-132 might regulate C1q expression in AD.

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Association Between CSF Beta-Amyloid and Apathy in Early-Stage Alzheimer Disease

Journal of Geriatric Psychiatry and Neurology ◽

10.1177/0891988719838627 ◽

2019 ◽

Vol 32 (3) ◽

pp. 164-169 ◽

Cited By ~ 1

Author(s):

A. Vergallo ◽

L. Giampietri ◽

C. Pagni ◽

F. S. Giorgi ◽

V. Nicoletti ◽

...

Keyword(s):

Early Stage ◽

Clinical Feature ◽

Csf Biomarkers ◽

Potential Association ◽

Modifying Effect ◽

Amyloid Aβ ◽

Β Amyloid ◽

Item Scores ◽

T Tau ◽

Late Stages

Aim: The apathetic syndrome is a common clinical feature in patients with Alzheimer diseases (AD), from preclinical phases to late stages of dementia, and it is strongly related to major disease outcomes. Unfortunately, no specific pharmacological treatments for apathy have been accomplished so far. Translational evidences have previously shown that a link between apathy and hallmarks of AD-related pathophysiology, that is, β-amyloid (Aβ) plaques and neurofibrillary tangles, exists. However, only few studies investigated the association between core biomarkers of AD and apathy scores, finding conflicting results. Methods: Thirty-seven patients were identified as having AD dementia according to National Institute on Aging–Alzheimer Association 2011 criteria. All participants underwent an extensive diagnostic workup including cerebrospinal fluid (CSF) assessment to measure the concentrations of Aβ42, t-tau, and pTau181. To follow, they were stratified as: apathy absence, apathy mild, and apathy severe according to the Neuro Psychiatric Inventory-apathy item scores. We investigated for potential associations between apathy scores and CSF biomarkers concentrations as well as for differences in terms of clinical and CSF biomarkers data across the 3 apathy groups. Results: The CSF Aβ42 concentrations were negatively correlated with apathy scores. In addition, patients with severe apathy had significantly lower Aβ42 levels compared to nonapathetic ones. Conclusion: Based on our results, we encourage further studies to untangle the potential association between the complex pathophysiological dynamics of AD and apathy which may represent an innovative reliable clinical outcome measure to use in clinical trials, investigating treatments with either a symptomatic or a disease-modifying effect.

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Dementia Cafés as a Community Resource for Persons With Early-Stage Cognitive Disorders: A Nationwide Survey in Japan

Journal of the American Medical Directors Association ◽

10.1016/j.jamda.2019.04.017 ◽

2019 ◽

Vol 20 (12) ◽

pp. 1515-1520 ◽

Cited By ~ 5

Author(s):

Hajime Takechi ◽

Tomoyuki Yabuki ◽

Masahiko Takahashi ◽

Hisao Osada ◽

Shinji Kato

Keyword(s):

Early Stage ◽

Cognitive Disorders ◽

Nationwide Survey ◽

Community Resource

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Bio-Inspired Robotic Solutions for Landslide Monitoring

Energies ◽

10.3390/en12071256 ◽

2019 ◽

Vol 12 (7) ◽

pp. 1256 ◽

Cited By ~ 1

Author(s):

Luca Patané

Keyword(s):

Mechanical Design ◽

Early Stage ◽

Smart Sensors ◽

Landslide Monitoring ◽

Dynamic Simulations ◽

Area Of Interest ◽

Landslide Event ◽

The Status ◽

Design Systems ◽

Target Locations

Bio-inspired solutions are often taken into account to solve problems that nature took millions of years to deal with. In the field of robotics, when we need to design systems able to perform in unstructured environments, bio-inspiration can be a useful instrument both for mechanical design and for the control architecture. In the proposed work the problem of landslide monitoring is addressed proposing a bio-inspired robotic structure developed to deploy a series of smart sensors on target locations with the aim of creating a sensor network capable of acquiring information on the status of the area of interest. The acquired data can be used both to create models and to generate alert signals when a landslide event is identified in the early stage. The design process of the robotic system, including dynamic simulations and robot experiments, will be presented here.

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The Proteome of the Dentate Terminal Zone of the Perforant Path Indicates Presynaptic Impairment in Alzheimer Disease

Molecular & Cellular Proteomics ◽

10.1074/mcp.ra119.001737 ◽

2019 ◽

Vol 19 (1) ◽

pp. 128-141 ◽

Cited By ~ 5

Author(s):

Hazal Haytural ◽

Georgios Mermelekas ◽

Ceren Emre ◽

Saket Milind Nigam ◽

Steven L. Carroll ◽

...

Keyword(s):

Alzheimer Disease ◽

Dentate Gyrus ◽

Molecular Mechanisms ◽

Molecular Layer ◽

Synaptic Proteins ◽

Perforant Path ◽

Synaptic Dysfunction ◽

Complexin 2 ◽

Terminal Zone ◽

Vesicle Cycle

Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to network disturbances and cognitive decline. Some synapses are more vulnerable than others, including the synapses of the perforant path, which provides the main excitatory input to the hippocampus. To elucidate the molecular mechanisms underlying the dysfunction of these synapses, we performed an explorative proteomic study of the dentate terminal zone of the perforant path. The outer two-thirds of the molecular layer of the dentate gyrus, where the perforant path synapses are located, was microdissected from five subjects with AD and five controls. The microdissected tissues were dissolved and digested by trypsin. Peptides from each sample were labeled with different isobaric tags, pooled together and pre-fractionated into 72 fractions by high-resolution isoelectric focusing. Each fraction was then analyzed by liquid chromatography-mass spectrometry. We quantified the relative expression levels of 7322 proteins, whereof 724 showed significantly altered levels in AD. Our comprehensive data analysis using enrichment and pathway analyses strongly indicated that presynaptic signaling, such as exocytosis and synaptic vesicle cycle processes, is severely disturbed in this area in AD, whereas postsynaptic proteins remained unchanged. Among the significantly altered proteins, we selected three of the most downregulated synaptic proteins; complexin-1, complexin-2 and synaptogyrin-1, for further validation, using a new cohort consisting of six AD and eight control cases. Semi-quantitative analysis of immunohistochemical staining confirmed decreased levels of complexin-1, complexin-2 and synaptogyrin-1 in the outer two-thirds of the molecular layer of the dentate gyrus in AD. Our in-depth proteomic analysis provides extensive knowledge on the potential molecular mechanism underlying synaptic dysfunction related to AD and supports that presynaptic alterations are more important than postsynaptic changes in early stages of the disease. The specific synaptic proteins identified could potentially be targeted to halt synaptic dysfunction in AD.

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A Simulation Study of Wireless Network Performance

Applied Mechanics and Materials ◽

10.4028/www.scientific.net/amm.679.176 ◽

2014 ◽

Vol 679 ◽

pp. 176-183

Author(s):

Ahmad Zulhusny Rozali ◽

Robert Stewart ◽

Sean Kennedy

Keyword(s):

Data Collection ◽

Real Time ◽

Wireless Network ◽

Simulation Study ◽

Network Performance ◽

Early Stage ◽

Reliable Data ◽

Future Research ◽

Area Of Interest

WSN technology has now become ubiquitous due to its flexibility, efficiency and affordability. For example the nodes in a WSN can be easily deployed in any targeted area and last for many years. The nodes can supply reliable data from within the environment with minimal disturbance to the target area.However challenges remain in providing real-time communication in some communication hostile conditions. It may not always be possible to leave the sensors in situ but instead data collection is through the use of mobile a WSN. For example as a vehicle fitted with sensing devices passes through an area of interest data is collected and relayed at certain gateway nodes back to a backhaul network for processing.In this paper our aim is to analyse the interference caused by a mobile jammer node to the stationary transmitter and receiver nodes in a network by using the OPNET Modeler software. This is early stage work aimed at developing a mobile WSN node in our future research.

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