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

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.

scholarly journals Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Male and Female Mice

2020 ◽  
Author(s):  
Andrea Stojakovic ◽  
Su-Youne Chang ◽  
Jarred Nesbitt ◽  
Nicholas P. Pichurin ◽  
Mark A. Ostroot ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Glucose Metabolism ◽  
Complex I ◽  
Energy Homeostasis ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Morris Water Maze Test ◽  
Synaptic Dysfunction ◽  
Male And Female ◽  
The Brain

AbstractBackgroundAccumulation of hyperphosphorylated Tau (pTau) protein is associated with synaptic dysfunction in Alzheimer’s disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown.ObjectiveTo investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on pTau levels, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms.MethodsCP2 was administered to male and female 3xTg-AD mice from 3.5 - 18 months of age. Cognitive function was assessed using the Morris water maze test. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting.ResultsChronic CP2 treatment restored synaptic activity and cognitive function, increased levels of synaptic proteins, improved glucose metabolism and energy homeostasis in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β).ConclusionCP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for AD.

scholarly journals Fluid Biomarkers for Synaptic Dysfunction and Loss

2020 ◽  
Vol 15 ◽  
pp. 117727192095031
Author(s):  
Elena Camporesi ◽  
Johanna Nilsson ◽  
Ann Brinkmalm ◽  
Bruno Becker ◽  
Nicholas J Ashton ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Early Stage ◽  
Cognitive Disorders ◽  
Synaptic Proteins ◽  
Synaptic Dysfunction ◽  
Csf Biomarkers ◽  
Area Of Interest ◽  
Synaptic Degeneration ◽  
Synaptic Pathology ◽  
Specific Disorders

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.

Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011937
Author(s):  
Gregory Scott Day ◽  
Melanie Y Yarbrough ◽  
Peter MD Körtvelyessy ◽  
Harald Prüss ◽  
Robert C Bucelli ◽  
...  
Keyword(s):  
Disease Severity ◽  
Synaptic Function ◽  
Synaptic Dysfunction ◽  
Csf Biomarkers ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Cognitively Normal ◽  
Surface Receptors ◽  
Total Tau ◽  
Normal Individuals

Objectives:To determine whether neuronal and neuroaxonal injury, neuroinflammation and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals.Methods:Biomarkers of neuronal (total-tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40) and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n=34) or LGI1/CASPR-2 (n=11) AME, and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scores were evaluated in a subset (n=20) of longitudinally followed patients.Results:Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, while markers of neuronal injury and synaptic function were stable (total-tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated cases from cognitively normal individuals (AUC=0.99; 95%CI: 0.97, >0.99). Younger age (ρ=-0.56; p=0.01), lower VILIP-1 (ρ=-0.60; p<0.01) and SNAP-25 (ρ=-0.54; p=0.01), and higher log10(YKL-40/SNAP-25) [(ρ=0.48; p=0.04] associated with greater disease severity (higher modified Rankin Score) in prospectively followed patients. Higher YKL-40 (ρ=0.60; p=0.02) and neurogranin (ρ=0.55; p=0.03) at presentation were associated with higher modified Rankin Scores 12-months following hospital discharge.Conclusions:CSF biomarkers suggest that neuronal integrity is acutely maintained in AME patients, despite neuroaxonal compromise. Low-levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell-surface receptors, and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.

scholarly journals Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice

2021 ◽  
Vol 79 (1) ◽  
pp. 335-353 ◽  
Author(s):  
Andrea Stojakovic ◽  
Su-Youne Chang ◽  
Jarred Nesbitt ◽  
Nicholas P. Pichurin ◽  
Mark A. Ostroot ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Glucose Metabolism ◽  
Complex I ◽  
Energy Homeostasis ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Synaptic Proteins ◽  
Synaptic Dysfunction ◽  
Male And Female ◽  
The Brain

Background: Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer’s disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. Objective: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. Methods: CP2 was administered to male and female 3xTg-AD mice from 3.5–18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Results: Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β). Conclusion: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.

scholarly journals MicroRNAs as Diagnostic Tools in Hepatocellular Carcinoma

2021 ◽  
Vol 3 (4) ◽  
pp. 237-246
Author(s):  
Jessica Evangelista ◽  
Elisa Zaninotto ◽  
Annalisa Gaglio ◽  
Michele Ghidini ◽  
Lucrezia Raimondi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Sample Size ◽  
Expression Patterns ◽  
Critical Role ◽  
Measurement Techniques ◽  
Small Sample ◽  
Diagnostic Tools ◽  
Migration And Invasion ◽  
Altered Expression ◽  
Liver Cancers

Liver cancer is the fourth leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 80% of all liver cancers. The serum concentration of alpha-fetoprotein (AFP) is the only validated biomarker for HCC diagnosis. MicroRNAs (miRNAs) are small non-coding RNAs of 21–30 nucleotides playing a critical role in human carcinogenesis, with types of miRNAs with oncogenic (oncomiRs) or tumor suppressor features. The altered expression of miRNAs in HCC is associated with many pathological processes, such as cancer initiation, tumor growth, apoptosis escape, promotion of migration and invasion. Moreover, circulating miRNAs have been increasingly investigated as non-invasive biomarkers for HCC diagnosis. MiRNAs’ expression patterns are altered in HCC and several single miRNAs or miRNAs panels have been found significantly up or downregulated in HCC with respect to healthy controls or non-oncological patients (cirrhotic or with viral hepatitis). However, any of the investigated miRNAs or miRNAs panels has entered clinical practice so far. This has mostly to do with lack of protocols standardization, small sample size and discrepancies in the measurement techniques. This review summarizes the major findings regarding the diagnostic role of miRNAs in HCC and their possible use together with standard biomarkers in order to obtain an early diagnosis and easier differential diagnosis from non-cancerous liver disease.

scholarly journals Blood RNA signatures predict recent tuberculosis exposure in mice, macaques and humans

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Russell C. Ault ◽  
Colwyn A. Headley ◽  
Alexander E. Hare ◽  
Bridget J. Carruthers ◽  
Asuncion Mejias ◽  
...  
Keyword(s):  
Disease Risk ◽  
Expression Patterns ◽  
Clinical Risk Factor ◽  
Late Time ◽  
Prognostic Information ◽  
Recent Infection ◽  
Household Contacts ◽  
Recent Transmission ◽  
Cynomolgus Macaques ◽  
Work Supports

Abstract Tuberculosis (TB) is the leading cause of death due to a single infectious disease. Knowing when a person was infected with Mycobacteriumtuberculosis (M.tb) is critical as recent infection is the strongest clinical risk factor for progression to TB disease in immunocompetent individuals. However, time since M.tb infection is challenging to determine in routine clinical practice. To define a biomarker for recent TB exposure, we determined whether gene expression patterns in blood RNA correlated with time since M.tb infection or exposure. First, we found RNA signatures that accurately discriminated early and late time periods after experimental infection in mice and cynomolgus macaques. Next, we found a 6-gene blood RNA signature that identified recently exposed individuals in two independent human cohorts, including adult household contacts of TB cases and adolescents who recently acquired M.tb infection. Our work supports the need for future longitudinal studies of recent TB contacts to determine whether biomarkers of recent infection can provide prognostic information of TB disease risk in individuals and help map recent transmission in communities.

scholarly journals Sleep-wake cycles drive daily dynamics of synaptic phosphorylation

Science ◽  
2019 ◽  
Vol 366 (6462) ◽  
pp. eaav3617 ◽  
Author(s):  
Franziska Brüning ◽  
Sara B. Noya ◽  
Tanja Bange ◽  
Stella Koutsouli ◽  
Jan D. Rudolph ◽  
...  
Keyword(s):  
Brain Function ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Regulation Of Transcription ◽  
Protein Abundance ◽  
Cellular Processes ◽  
Cytoskeleton Reorganization ◽  
And Function ◽  
Daily Changes ◽  
Rest Activity

The circadian clock drives daily changes of physiology, including sleep-wake cycles, through regulation of transcription, protein abundance, and function. Circadian phosphorylation controls cellular processes in peripheral organs, but little is known about its role in brain function and synaptic activity. We applied advanced quantitative phosphoproteomics to mouse forebrain synaptoneurosomes isolated across 24 hours, accurately quantifying almost 8000 phosphopeptides. Half of the synaptic phosphoproteins, including numerous kinases, had large-amplitude rhythms peaking at rest-activity and activity-rest transitions. Bioinformatic analyses revealed global temporal control of synaptic function through phosphorylation, including synaptic transmission, cytoskeleton reorganization, and excitatory/inhibitory balance. Sleep deprivation abolished 98% of all phosphorylation cycles in synaptoneurosomes, indicating that sleep-wake cycles rather than circadian signals are main drivers of synaptic phosphorylation, responding to both sleep and wake pressures.

scholarly journals AMPA receptors in the synapse turnover by monomer diffusion

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jyoji Morise ◽  
Kenichi G. N. Suzuki ◽  
Ayaka Kitagawa ◽  
Yoshihiko Wakazono ◽  
Kogo Takamiya ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Ampa Receptors ◽  
Single Molecules ◽  
Lateral Diffusion ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Monomer Diffusion

AbstractThe number and subunit compositions of AMPA receptors (AMPARs), hetero- or homotetramers composed of four subunits GluA1–4, in the synapse is carefully tuned to sustain basic synaptic activity. This enables stimulation-induced synaptic plasticity, which is central to learning and memory. The AMPAR tetramers have been widely believed to be stable from their formation in the endoplasmic reticulum until their proteolytic decomposition. However, by observing GluA1 and GluA2 at the level of single molecules, we find that the homo- and heterotetramers are metastable, instantaneously falling apart into monomers, dimers, or trimers (in 100 and 200 ms, respectively), which readily form tetramers again. In the dendritic plasma membrane, GluA1 and GluA2 monomers and dimers are far more mobile than tetramers and enter and exit from the synaptic regions. We conclude that AMPAR turnover by lateral diffusion, essential for sustaining synaptic function, is largely done by monomers of AMPAR subunits, rather than preformed tetramers.

Novel PKD1 Mutations in Patients with Autosomal Dominant Polycystic Kidney Disease

2020 ◽  
Author(s):  
Hyerin Kim ◽  
Hyung-Hoi Kim ◽  
Chulhun L Chang ◽  
Sang Heon Song ◽  
Namhee Kim
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Genetic Diagnosis ◽  
Diagnostic Tools ◽  
Polycystic Kidney ◽  
Prognostic Information ◽  
Panel Test ◽  
Autosomal Dominant Polycystic Kidney ◽  
Clinically Significant

Abstract Objective Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. Identifying mutated causative genes can provide diagnostic and prognostic information. In this study, we describe the clinical application of a next generation sequencing (NGS)-based, targeted multi-gene panel test for the genetic diagnosis of patients with ADPKD. Methods We applied genetic analysis on 26 unrelated known or suspected patients with ADPKD. A total of 10 genes related to cystic change of kidney were targeted. Detected variants were classified according to standard guidelines. Results We identified 19 variants (detection rate: 73.1%), including PKD1 (n = 18) and PKD2 (n = 1). Of the 18 PKD1 variants, 8 were novel. Conclusion Multigene panel test can be a comprehensive tool in a clinical setting for genetic diagnosis of ADPKD. It allows us to identify clinically significant novel variants and confirm the diagnosis, and these objectives are difficult to achieve using conventional diagnostic tools.

Synaptopathy: dysfunction of synaptic function?

2010 ◽  
Vol 38 (2) ◽  
pp. 443-444 ◽  
Author(s):  
Nils Brose ◽  
Vincent O'Connor ◽  
Paul Skehel
Keyword(s):  
Animal Experimentation ◽  
Structure And Function ◽  
Synaptic Function ◽  
Cellular Systems ◽  
Brain Diseases ◽  
Psychiatric Disease ◽  
Synaptic Dysfunction ◽  
A Value ◽  
Synaptic Structure ◽  
And Function

Synaptopathy is an increasingly popular term used to define key features of neurodegenerative and psychiatric disease. It implies that disruptions in synaptic structure and function are potentially the major determinant of such brain diseases. The Synaptopathies: Dysfunction of Synaptic Function Biochemical Society Focused Meeting brought together several invited speakers, supplemented with short communications from young scientists, who addressed this possibility. The talks spanned the full gamut of approaches that brought molecular, cellular, systems and whole-animal experimentation together to address how fundamental synaptic biology was increasingly informing on dysfunction in disease. The disease and models thereof discussed included Alzheimer's disease, prions, Huntington's disease, Parkinson's disease, schizophrenia and autism. The audience were asked to reflect on whether synaptopathy, although attractive and conceptually useful, provided a significant explanation as the cause of these major diseases. The breadth of the meeting reinforced the complexity of these brain diseases, supported the significance of synaptic dysfunction in disease, but left open the issue as to whether the prime cause of these disorders could be resolved as simple synaptic dysfunction. Thus, despite revealing a value of synaptopathy, further investigation will be required to reveal its balance in the cause and effect in each of the major brain diseases.

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