scholarly journals Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 686
Author(s):  
Maria Concetta Geloso ◽  
Nadia D’Ambrosi
Keyword(s):  
Multiple Sclerosis ◽  
Neuronal Death ◽  
Environmental Changes ◽  
Experimental Models ◽  
Synaptic Dysfunction ◽  
Synapse Elimination ◽  
Neurodegenerative Process ◽  
Immune Mediated ◽  
Wide Range ◽  
Demyelinating Lesions

Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models.

Information and resources important to the quality of life of people living with multiple sclerosis

2020 ◽  
Vol 26 (2) ◽  
pp. 92-104
Author(s):  
Malachy Bishop ◽  
Stuart Rumrill ◽  
Bradley McDaniels ◽  
Jian Li ◽  
Robert Fraser ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Sclerosis ◽  
Psychosocial Health ◽  
Physical And Mental Health ◽  
Psychosocial Effects ◽  
Immune Mediated ◽  
Wide Range ◽  
The Central Nervous System ◽  
Types Of Information

AbstractMultiple sclerosis (MS) is a chronic, typically progressive immune-mediated disease characterized by inflammation and demyelination in the central nervous system (CNS), and is associated with a wide range of neurological, physical, and psychosocial effects. For people living with MS, access to relevant, timely, and accessible health information and resources may contribute to effective illness management, psychosocial health, and quality of life (QOL). In this study, we sought to increase understanding of the specific types of information most wanted by people with MS, as well as the sources and effects of this information. Specifically, we surveyed 748 adults with MS about (a) the sources from which they obtain information about MS, (b) the type of information that is most important in terms of improving their QOL, and (c) specific topics about which they would like to have more information, services, or resources. Content analysis of the qualitative results demonstrated the diversity of information sources accessed by people with MS and the importance of providing information through different formats and media. The participants prioritized information related to new MS medications and treatments, physical and mental health and wellness, and local opportunities for support. Implications for practicing rehabilitation counselors are discussed.

scholarly journals Cuprizone and EAE mouse frontal cortex proteomics revealed proteins altered in multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eystein Oveland ◽  
Intakhar Ahmad ◽  
Ragnhild Reehorst Lereim ◽  
Ann Cathrine Kroksveen ◽  
Harald Barsnes ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Frontal Cortex ◽  
Neurological Diseases ◽  
Experimental Models ◽  
Label Free ◽  
Immune Mediated ◽  
Multiple Sclerosis Patients ◽  
Protein Alterations ◽  
Disease Stages ◽  
Fluid Levels

AbstractTwo pathophysiological different experimental models for multiple sclerosis were analyzed in parallel using quantitative proteomics in attempts to discover protein alterations applicable as diagnostic-, prognostic-, or treatment targets in human disease. The cuprizone model reflects de- and remyelination in multiple sclerosis, and the experimental autoimmune encephalomyelitis (EAE, MOG1-125) immune-mediated events. The frontal cortex, peripheral to severely inflicted areas in the CNS, was dissected and analyzed. The frontal cortex had previously not been characterized by proteomics at different disease stages, and novel protein alterations involved in protecting healthy tissue and assisting repair of inflicted areas might be discovered. Using TMT-labelling and mass spectrometry, 1871 of the proteins quantified overlapped between the two experimental models, and the fold change compared to controls was verified using label-free proteomics. Few similarities in frontal cortex between the two disease models were observed when regulated proteins and signaling pathways were compared. Legumain and C1Q complement proteins were among the most upregulated proteins in cuprizone and hemopexin in the EAE model. Immunohistochemistry showed that legumain expression in post-mortem multiple sclerosis brain tissue (n = 19) was significantly higher in the center and at the edge of white matter active and chronic active lesions. Legumain was associated with increased lesion activity and might be valuable as a drug target using specific inhibitors as already suggested for Parkinson’s and Alzheimer’s disease. Cerebrospinal fluid levels of legumain, C1q and hemopexin were not significantly different between multiple sclerosis patients, other neurological diseases, or healthy controls.

Dysregulation of SIRT-1 Signaling in Multiple Sclerosis and Neuroimmune Disorders: A Systematic Review on SIRTUIN Activators as Potential Immunomodulators and Influences on other Dysfunctions

2021 ◽  
Vol 21 ◽  
Author(s):  
Nidhi Sharma ◽  
Ambika Shandilya ◽  
Nitish Kumar ◽  
Sidharth Mehan
Keyword(s):  
Multiple Sclerosis ◽  
Transcription Factors ◽  
Neuronal Apoptosis ◽  
Management Strategies ◽  
Clinical Findings ◽  
Therapeutic Interventions ◽  
Molecular Alterations ◽  
Current Review ◽  
Immune Mediated ◽  
Wide Range

: Immune dysregulation, neuronal inflammation, and oligodendrocyte degradation are key causes for autoimmune disorders like multiple sclerosis (MS) and various otherimmune dysregulated neurodegenerative complications responsible for CNS-mediated immune responses.Sirtuins (SIRT-1) is nicotinamide adenosine dinucleotide (NAD)-dependent transcriptional protein thatdeacetylases and removes acetyl groups from its transcription factors like P53, FOXO, NF-Κb, PGC-1α. SIRT-1 mediates a wide range of physiological functions,including gene transcription, metabolism, neuronal apoptosis, and glucose production.SIRT-1 dysregulation targets transcription factors,and other molecular alterations such as gene expression modification influence neuronal plasticity, inhibits Th17 cells, and interleukin-1β can aggravate brain diseases.Preclinical and clinical findings show that the upregulation of SIRT-1 reduces autoimmunity, neurodegeneration, and neuroexcitation. Even though drugs are being developed for symptomatic therapies in clinical trials, there are particular pharmacological implications for improving post-operative conditions in neurodegenerativepatients where intensive care is required.Understanding the SIRT-1 signaling and identifying immune-mediated neuron deterioration can detect major therapeutic interventions that could prevent neurocomplications.Thus, in the current review, we have addressed the manifestations of disease by the downregulation of SIRT-1 that could potentially cause MS and other neurodegenerative disorders and provided data on existing available and effective drug therapies and disease management strategies.

Expression of semaphorin 3A, semaphorin 7A and their receptors in multiple sclerosis lesions

2015 ◽  
Vol 21 (13) ◽  
pp. 1632-1643 ◽  
Author(s):  
C Costa ◽  
E Martínez-Sáez ◽  
A Gutiérrez-Franco ◽  
H Eixarch ◽  
Z Castro ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Critical Role ◽  
Experimental Models ◽  
Reactive Astrocytes ◽  
Demyelinating Diseases ◽  
Inflammatory Activity ◽  
Β1 Integrin ◽  
Neuropilin 1 ◽  
Ability To Regenerate ◽  
Demyelinating Lesions

Background: Studies in multiple sclerosis (MS) and in experimental models point to a critical role of semaphorin (sema)3A and sema7A in MS pathogenesis. Objective: The objective of this paper is to characterise the expression of sema3A, sema7A, and their receptors in MS lesions. Methods: We included 44 demyelinating lesions from MS patients, 12 lesions with acute cerebral infarct, 11 lesions with progressive multifocal leucoencephalopathy and 10 non-neurological control patients. MS lesions were classified according to inflammatory activity and all samples were immunostained for sema3A, sema7A, neuropilin 1 (Np-1), α1-integrin, and β1-integrin. Results: In MS-damaged white matter sema3A and Np-1 were both detected in microglia/macrophages, whereas reactive astrocytes expressed only sema3A. Otherwise, sema7A, α1-integrin and β1-integrin were observed in reactive astrocytes, and microglia/macrophages only expressed β1-integrin. The expression of sema3A, sema7A and their receptors is more relevant in MS than in other demyelinating diseases. Sema3A and sema7A expression correlated with the inflammatory activity of the MS lesions, suggesting their involvement in the immunological process that takes place in MS. Conclusions: The expression pattern of sema3A, sema7A and their receptors in MS lesions suggests that both molecules contribute to create a negative environment for tissue regeneration, influencing the ability to regenerate the damaged tissue.

scholarly journals Theiler's Virus Infection: a Model for Multiple Sclerosis

2004 ◽  
Vol 17 (1) ◽  
pp. 174-207 ◽  
Author(s):  
Emilia L. Oleszak ◽  
J. Robert Chang ◽  
Herman Friedman ◽  
Christos D. Katsetos ◽  
Chris D. Platsoucas
Keyword(s):  
Multiple Sclerosis ◽  
Demyelinating Disease ◽  
Molecular Mimicry ◽  
Experimental Models ◽  
Demyelinating Diseases ◽  
Acute Disease ◽  
Theiler's Virus ◽  
Spinal Cord Atrophy ◽  
Demyelinating Lesions ◽  
Mononuclear Cell Infiltrates

SUMMARY Both genetic background and environmental factors, very probably viruses, appear to play a role in the etiology of multiple sclerosis (MS). Lessons from viral experimental models suggest that many different viruses may trigger inflammatory demyelinating diseases resembling MS. Theiler's virus, a picornavirus, induces in susceptible strains of mice early acute disease resembling encephalomyelitis followed by late chronic demyelinating disease, which is one of the best, if not the best, animal model for MS. During early acute disease the virus replicates in gray matter of the central nervous system but is eliminated to very low titers 2 weeks postinfection. Late chronic demyelinating disease becomes clinically apparent approximately 2 weeks later and is characterized by extensive demyelinating lesions and mononuclear cell infiltrates, progressive spinal cord atrophy, and axonal loss. Myelin damage is immunologically mediated, but it is not clear whether it is due to molecular mimicry or epitope spreading. Cytokines, nitric oxide/reactive nitrogen species, and costimulatory molecules are involved in the pathogenesis of both diseases. Close similarities between Theiler's virus-induced demyelinating disease in mice and MS in humans, include the following: major histocompatibility complex-dependent susceptibility; substantial similarities in neuropathology, including axonal damage and remyelination; and paucity of T-cell apoptosis in demyelinating disease. Both diseases are immunologically mediated. These common features emphasize the close similarities of Theiler's virus-induced demyelinating disease in mice and MS in humans.

scholarly journals Kinematic Analysis of Lower Limb Joint Asymmetry during Gait in People with Multiple Sclerosis

Symmetry ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 598
Author(s):  
Massimiliano Pau ◽  
Bruno Leban ◽  
Michela Deidda ◽  
Federica Putzolu ◽  
Micaela Porta ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Lower Limb ◽  
Sagittal Plane ◽  
Cross Sectional Study ◽  
Camera Motion ◽  
Cross Sectional ◽  
Temporal Parameters ◽  
Wide Range ◽  
Edss Score ◽  
Spatio Temporal

The majority of people with Multiple Sclerosis (pwMS), report lower limb motor dysfunctions, which may relevantly affect postural control, gait and a wide range of activities of daily living. While it is quite common to observe a different impact of the disease on the two limbs (i.e., one of them is more affected), less clear are the effects of such asymmetry on gait performance. The present retrospective cross-sectional study aimed to characterize the magnitude of interlimb asymmetry in pwMS, particularly as regards the joint kinematics, using parameters derived from angle-angle diagrams. To this end, we analyzed gait patterns of 101 pwMS (55 women, 46 men, mean age 46.3, average Expanded Disability Status Scale (EDSS) score 3.5, range 1–6.5) and 81 unaffected individuals age- and sex-matched who underwent 3D computerized gait analysis carried out using an eight-camera motion capture system. Spatio-temporal parameters and kinematics in the sagittal plane at hip, knee and ankle joints were considered for the analysis. The angular trends of left and right sides were processed to build synchronized angle–angle diagrams (cyclograms) for each joint, and symmetry was assessed by computing several geometrical features such as area, orientation and Trend Symmetry. Based on cyclogram orientation and Trend Symmetry, the results show that pwMS exhibit significantly greater asymmetry in all three joints with respect to unaffected individuals. In particular, orientation values were as follows: 5.1 of pwMS vs. 1.6 of unaffected individuals at hip joint, 7.0 vs. 1.5 at knee and 6.4 vs. 3.0 at ankle (p < 0.001 in all cases), while for Trend Symmetry we obtained at hip 1.7 of pwMS vs. 0.3 of unaffected individuals, 4.2 vs. 0.5 at knee and 8.5 vs. 1.5 at ankle (p < 0.001 in all cases). Moreover, the same parameters were sensitive enough to discriminate individuals of different disability levels. With few exceptions, all the calculated symmetry parameters were found significantly correlated with the main spatio-temporal parameters of gait and the EDSS score. In particular, large correlations were detected between Trend Symmetry and gait speed (with rho values in the range of –0.58 to –0.63 depending on the considered joint, p < 0.001) and between Trend Symmetry and EDSS score (rho = 0.62 to 0.69, p < 0.001). Such results suggest not only that MS is associated with significantly marked interlimb asymmetry during gait but also that such asymmetry worsens as the disease progresses and that it has a relevant impact on gait performances.

Case Report: Delayed Alemtuzumab-Induced Concurrent Neutropenia and Thrombocytopenia in Relapsing-Remitting Multiple Sclerosis

2021 ◽  
pp. 089719002110212
Author(s):  
Akaansha Ganju ◽  
James C. Stock ◽  
Kim Jordan
Keyword(s):  
Multiple Sclerosis ◽  
Case Reports ◽  
Severe Neutropenia ◽  
Cell Counts ◽  
Immune Mediated ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Study Participants ◽  
Relapsing Remitting Multiple Sclerosis

Alemtuzumab is an anti-CD52 monoclonal antibody used to treat relapsing-remitting multiple sclerosis following failure of second-line medications. It is administered intravenously in 2 treatment sequences 1 year apart. This drug is frequently associated with mild infusion reactions within days of administration, increased infection risk, and long term adverse events from secondary autoimmunity. Alemtuzumab-induced serious immune-mediated thrombocytopenia (ITP) is well-reported and occurred in 1.0-2.2% of participants in initial phase 2 and 3 trials for multiple sclerosis. Significant neutropenia, however, is rare and was only observed in 0.1% of study participants. Delayed neutropenia and/or ITP is thought to occur from secondary autoimmunity. Few case reports have described severe neutropenia occurring beyond 2 months of last alemtuzumab dose. We present an unusual case of delayed combined neutropenia and thrombocytopenia that occurred 15 months after the second infusion of alemtuzumab. The patient was asymptomatic and presented following discovery of neutropenia and thrombocytopenia during routine laboratory studies. The patient responded to steroids initially and was discharged, although outpatient cell counts subsequently revealed recurrent neutropenia and ITP. The adverse drug reaction probability (Naranjo) scale was completed and showed probable likelihood that the adverse event was alemtuzumab-related. Long term screening for delayed hematologic abnormalities, at least 4 years after initial dose, is necessary when using alemtuzumab. Greater research is needed to understand the mechanism of drug-associated neutropenia.

scholarly journals NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Mariana Van Zeller ◽  
Diogo M. Dias ◽  
Ana M. Sebastião ◽  
Cláudia A. Valente
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Nlrp3 Inflammasome ◽  
Neuronal Death ◽  
Inflammatory Responses ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Wide Range

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

scholarly journals Identification of Putative Virulence Genes by DNA Methylation Studies in the Cereal Pathogen Fusarium graminearum

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1192
Author(s):  
Francesco Tini ◽  
Giovanni Beccari ◽  
Gianpiero Marconi ◽  
Andrea Porceddu ◽  
Micheal Sulyok ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fusarium Graminearum ◽  
Environmental Changes ◽  
Virulent Strain ◽  
Fungal Virulence ◽  
Wheat Seedlings ◽  
Wide Range ◽  
Conidia Production ◽  
Natural Hosts

DNA methylation mediates organisms’ adaptations to environmental changes in a wide range of species. We investigated if a such a strategy is also adopted by Fusarium graminearum in regulating virulence toward its natural hosts. A virulent strain of this fungus was consecutively sub-cultured for 50 times (once a week) on potato dextrose agar. To assess the effect of subculturing on virulence, wheat seedlings and heads (cv. A416) were inoculated with subcultures (SC) 1, 23, and 50. SC50 was also used to re-infect (three times) wheat heads (SC50×3) to restore virulence. In vitro conidia production, colonies growth and secondary metabolites production were also determined for SC1, SC23, SC50, and SC50×3. Seedling stem base and head assays revealed a virulence decline of all subcultures, whereas virulence was restored in SC50×3. The same trend was observed in conidia production. The DNA isolated from SC50 and SC50×3 was subject to a methylation content-sensitive enzyme and double-digest, restriction-site-associated DNA technique (ddRAD-MCSeEd). DNA methylation analysis indicated 1024 genes, whose methylation levels changed in response to the inoculation on a healthy host after subculturing. Several of these genes are already known to be involved in virulence by functional analysis. These results demonstrate that the physiological shifts following sub-culturing have an impact on genomic DNA methylation levels and suggest that the ddRAD-MCSeEd approach can be an important tool for detecting genes potentially related to fungal virulence.

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