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Frontiers in Immunology 2019Akt is a serine/threonine protein kinase that plays a major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved in apoptosis...
Akt is a serine/threonine protein kinase that plays a major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved in apoptosis and insulin signaling, respectively, the role for Akt3 remains uncertain. Akt3 is predominantly expressed in the brain, and total deletion of Akt3 in mice results in a reduction in brain size and neurodegeneration following injury. Previously, we found that Akt3 mice have a significantly worse clinical course during myelin-oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model in which autoreactive immune cells enter the CNS, resulting in inflammation, demyelination, and axonal injury. Spinal cords of Akt3 mice are severely demyelinated and have increased inflammation compared to WT, suggesting a neuroprotective role for Akt3 during EAE. To specifically address the role of Akt3 in neuroinflammation and maintaining neuronal integrity, we used several mouse strains with different manipulations to Akt3. During EAE, Akt3 mice (with enhanced Akt3 kinase activity) had lower clinical scores, a lag in disease onset, a delay in the influx of inflammatory cells into the CNS, and less axonal damage compared to WT mice. A significant increased efficiency of differentiation toward FOXP3 expressing iTregs was also observed in Akt3 mice relative to WT. Mice with a conditional deletion of Akt3 in CD4 T-cells had an earlier onset of EAE symptoms, increased inflammation in the spinal cord and brain, and had fewer FOXP3 cells and mRNA expression. No difference in EAE outcome was observed when Akt3 expression was deleted in neurons (Syn1-CKO). These results indicate that Akt3 signaling in T-cells and not neurons is necessary for maintaining CNS integrity during an inflammatory demyelinating disease.
Topics: Animals; Biomarkers; Demyelinating Diseases; Disease Models, Animal; Disease Susceptibility; Encephalomyelitis, Autoimmune, Experimental; Fluorescent Antibody Technique; Forkhead Transcription Factors; Immunohistochemistry; Immunophenotyping; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt; RNA, Messenger; Signal Transduction; Spinal Cord; T-Lymphocyte Subsets
PubMed: 31404142
DOI: 10.3389/fimmu.2019.01738 -
Journal of Neuroscience Research Jun 2023Oligodendrocytes are a type of glial cells that produce a lipid-rich membrane called myelin. Myelin assembles into a sheath and lines neuronal axons in the brain and... (Review)
Review
Oligodendrocytes are a type of glial cells that produce a lipid-rich membrane called myelin. Myelin assembles into a sheath and lines neuronal axons in the brain and spinal cord to insulate them. This not only increases the speed and efficiency of nerve signal transduction but also protects the axons from damage and degradation, which could trigger neuronal cell death. Demyelination, which is caused by a loss of myelin and oligodendrocytes, is a prominent feature of many neurological conditions, including Multiple sclerosis (MS), spinal cord injuries (SCI), and leukodystrophies. Demyelination is followed by a time of remyelination mediated by the recruitment of endogenous oligodendrocyte precursor cells, their migration to the injury site, and differentiation into myelin-producing oligodendrocytes. Unfortunately, endogenous remyelination is not sufficient to overcome demyelination, which explains why there are to date no regenerative-based treatments for MS, SCI, or leukodystrophies. To better understand the role of oligodendrocytes and develop cell-based remyelination therapies, human oligodendrocytes have been derived from somatic cells using cell reprogramming. This review will detail the different cell reprogramming methods that have been developed to generate human oligodendrocytes and their applications to disease modeling and cell-based remyelination therapies. Recent developments in the field have seen the derivation of brain organoids from pluripotent stem cells, and protocols have been devised to incorporate oligodendrocytes within the organoids, which will also be reviewed.
Topics: Humans; Remyelination; Cellular Reprogramming; Oligodendroglia; Myelin Sheath; Demyelinating Diseases; Spinal Cord Injuries; Multiple Sclerosis; Cell Differentiation
PubMed: 36749877
DOI: 10.1002/jnr.25173 -
Neuroscience Letters Sep 2019Inflammatory demyelinating processes target the neuron, particularly axons and synapses, in multiple sclerosis (MS). There is a gathering body of evidence indicating... (Review)
Review
Inflammatory demyelinating processes target the neuron, particularly axons and synapses, in multiple sclerosis (MS). There is a gathering body of evidence indicating molecular changes which converge on mitochondria within neurons in progressive forms of MS. The most reproducible changes are the increase in mitochondrial content within demyelinated axons and mitochondrial respiratory chain complex deficiency in neurons, which compromises the capacity to generate ATP. The resulting lack of ATP and the likely energy failure state and its coupling with an increase in demand for energy by the demyelinated axon, are particularly relevant to the long tracts such as corticospinal tracts with long projection axons. Recent work in our laboratory and that of our collaborators indicate the limited reflection of the mitochondrial changes within neurons in the experimental disease models. Enhancing the energy producing capacity of neurons to meet the increased energy demand of demyelinated axons is likely to be a novel neuroprotective strategy in progressive MS.
Topics: Animals; Axons; Demyelinating Diseases; Humans; Mitochondria; Mitochondrial Diseases; Multiple Sclerosis; Nerve Degeneration; Neurons
PubMed: 31082453
DOI: 10.1016/j.neulet.2019.05.012 -
Brain Research Oct 2020Numerous studies report that changes in extracellular matrix components and receptors, such as CD44, contribute to immune cell recruitment and thus lesion formation in...
Numerous studies report that changes in extracellular matrix components and receptors, such as CD44, contribute to immune cell recruitment and thus lesion formation in multiple sclerosis (MS). In the present study, we used the cuprizone model to elucidate the expression pattern of CD44 in a toxin-induced MS model. Therefore, tissues of cuprizone-intoxicated mice were analyzed by real-time qRT-PCR and immunohistochemical staining against CD44. Co-localization analyses of CD44-positive cells with glial cell markers were performed by immunofluorescence labeling and in-situ hybridization. To investigate the functional importance of CD44 expression for myelination and glial cell activation, Cd44-deficient mice were used. In this study we demonstrate that CD44 expression is induced in a time-dependent manner in an autoimmune-independent model of MS. Up-regulation of CD44 expression was primarily associated to the superficial and perivascular glia limitans and demyelinated white matter structures, particularly the corpus callosum. In the demyelinated corpus callosum, CD44 was localized on GFAP astrocytes and IBA1 microglial cells. Despite a robust expression induction, Cd44-deficiency did not ameliorate cuprizone-induced pathology. Although further studies will be needed to examine the functional relevance of CD44 in the cuprizone model, the spatial and temporal expression pattern of CD44 will pave the way to evaluate its precise role in different (immune and non-immune) pathological conditions.
Topics: Animals; Brain; Chelating Agents; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Hyaluronan Receptors; Mice; Mice, Inbred C57BL; Multiple Sclerosis; White Matter
PubMed: 32524994
DOI: 10.1016/j.brainres.2020.146950 -
Trends in Neurosciences Jun 2016Despite an appreciation of the importance of myelination and the consequences of pathological demyelination, the fundamental mechanisms regulating myelination are only... (Review)
Review
Despite an appreciation of the importance of myelination and the consequences of pathological demyelination, the fundamental mechanisms regulating myelination are only now being resolved. Neuronal activity has long been considered a plausible regulatory signal for myelination. However, controversy surrounding its dispensability in certain contexts and the difficulty in determining to what degree it influences myelination has limited its widespread acceptance. Recent studies have shed new light on the role of neuronal activity in regulating oligodendrogenesis and myelination. Further, the dynamics of myelin in adulthood and the association between skilled learning and myelination have become increasingly well characterized. These advances present new considerations for the management of multiple sclerosis and open up new approaches to facilitate remyelination following pathological demyelination.
Topics: Animals; Axons; Demyelinating Diseases; Humans; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Regeneration
PubMed: 27113322
DOI: 10.1016/j.tins.2016.04.003 -
Journal of the Neurological Sciences Apr 2016Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe... (Observational Study)
Observational Study
Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe the clinical features, diagnostic results, treatment and outcomes in a large cohort of patients with CCPD. Thirty-one patients entered this retrospective, observational, two-center study. In 20 patients (65%) CCPD presented, after an infection, as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barré syndrome. Demyelinating features of peripheral nerve damage fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria for CIDP were found in 23 patients (74%), and spatial dissemination of demyelinating lesions on brain MRI fulfilling the 2010 McDonald criteria for multiple sclerosis (MS) in 11 (46%). Two thirds of the patients had a relapsing or progressive disease course, usually related to the appearance of new spinal cord lesions or worsening of the peripheral neuropathy, and showed unsatisfactory responses to high-dose corticosteroids and intravenous immunoglobulins. The clinical presentation of CCPD was severe in 22 patients (71%), who were left significantly disabled. Our data suggest that CCPD has heterogeneous features and shows frequent post-infectious onset, primary peripheral nervous system or central nervous system involvement, a monophasic or chronic disease course, inadequate response to treatments, and a generally poor outcome. We therefore conclude that the current diagnostic criteria for MS and CIDP may not fully encompass the spectrum of possible manifestations of CCPD, whose pathogenesis remains largely unknown.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cohort Studies; Demyelinating Diseases; Female; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Polyradiculoneuropathy; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Retrospective Studies; Treatment Outcome; Young Adult
PubMed: 27000248
DOI: 10.1016/j.jns.2016.02.022 -
Methods in Molecular Biology (Clifton,... 2018Autophagy is a key cellular mechanism involved in the degradation of long-lived proteins and organelles. We and others have previously shown that Schwann cells are able...
Autophagy is a key cellular mechanism involved in the degradation of long-lived proteins and organelles. We and others have previously shown that Schwann cells are able to degrade their own myelin by a form of selective autophagy, or myelinophagy. There is now increasing evidence that myelinophagy could also be aberrantly activated in other demyelinating diseases, including hereditary or inflammatory neuropathies, implicating this pathway in the pathogenesis of these disorders. In this chapter, we describe our protocol to monitor autophagy in peripheral nerves, using the autophagy flux assay. This assay can be useful to compare basal and demyelination-induced autophagy in genetic mice models, or after treatment with specific compounds.
Topics: Animals; Animals, Newborn; Autophagy; Cell Culture Techniques; Demyelinating Diseases; Lysosomes; Mice; Microtubule-Associated Proteins; Rats; Schwann Cells
PubMed: 30006711
DOI: 10.1007/978-1-4939-7862-5_15 -
Frontiers of Hormone Research 2019A time-dependent loss of cell solute protects against lethal cerebral edema in hyponatremia. This adaptation, which makes survival possible when the serum sodium... (Review)
Review
A time-dependent loss of cell solute protects against lethal cerebral edema in hyponatremia. This adaptation, which makes survival possible when the serum sodium concentration is extremely low, also makes the brain vulnerable to injury if chronic (>48 hours) hyponatremia is corrected more rapidly than lost brain solutes can be recovered. Rapid correction of chronic hyponatremia results in programmed cell death of astrocytes and oligodendrocytes and presents clinically with a delayed onset of neurological findings, known as the osmotic demyelination syndrome. This iatrogenic complication can be avoided by limiting correction of hyponatremia to <8 mEq/L per day.
Topics: Demyelinating Diseases; Humans; Hyponatremia; Iatrogenic Disease
PubMed: 32097948
DOI: 10.1159/000493243 -
Molecular Neurobiology Jan 2016Despite a large amount of research which aims at defining the pathophysiology of human demyelination (i.e., multiple sclerosis), etiological bases of disease have been... (Review)
Review
Despite a large amount of research which aims at defining the pathophysiology of human demyelination (i.e., multiple sclerosis), etiological bases of disease have been unknown so far. The point of intersection of all assumed etiological factors, which are mainly based upon immunological cascades, is neuroinflammation. The precise definition of the place and role of all pathogenetic factors in the occurrence and development of the disease is of crucial importance for understanding the clinical nature and for finding more effective therapeutic options. There are few studies whose results give more precise data about the role and the importance of other factors in neuroinflammation, besides immunological ones, with regard to clinical and paraclinical correlates of the disease. The review integrates results found in previously performed studies which have evaluated oxidative stress participation in early and late neuroinflammation. The largest number of studies indicates that the use of antioxidants affects the change of neuroinflammation course under experimental conditions, which is reflected in the reduction of the severity and the total reversibility in clinical presentation of the disease, the faster achieving of remission, and the delayed and slow course of neuroinflammation. Therapies based on the knowledge of redox biology targeting free radical generation hold great promise in modulation of the neuroinflammation and its clinical presentations.
Topics: Animals; Demyelinating Diseases; Humans; Inflammation Mediators; Lipid Peroxidation; Oxidative Stress
PubMed: 25502298
DOI: 10.1007/s12035-014-9041-x -
Multiple Sclerosis (Houndmills,... Oct 2022Haemorrhagic demyelinating lesions are rare, and little is known about the demyelinating diseases with which they are associated, or how lesional haemorrhage affects...
BACKGROUND
Haemorrhagic demyelinating lesions are rare, and little is known about the demyelinating diseases with which they are associated, or how lesional haemorrhage affects treatment and outcomes.
OBJECTIVE
To examine the clinical characteristics and outcomes of patients with demyelinating lesions and magnetic resonance imaging (MRI) evidence of haemorrhage seen at the Mayo clinic between 1990 and 2018.
METHODS
The Mayo Clinic's medical-record diagnostic-linkage system was used to identify patients with CNS demyelinating disease and parenchymal haemorrhage on brain MRI cross-referenced against a database of patients with pathologically confirmed CNS demyelinating disease. The clinical characteristics, diagnosis, MRI findings, brain histopathology, and outcomes of these patients were reviewed.
RESULTS
Ten patients with haemorrhagic demyelination were identified, including three patients who underwent a brain biopsy. The main findings were that haemorrhagic demyelinating lesions most often occur in atypical forms of demyelination, especially acute haemorrhagic leukoencephalitis (AHL, or Weston-Hurst disease) and tumefactive demyelination, and rarely in multiple sclerosis. A spectrum of outcomes was observed for these patients ranging from complete remission through to high level disability.
CONCLUSION
Lesional haemorrhage is uncommon in demyelinating disease where it is most closely associated with AHL. Bleeding within a demyelinating lesion does not always herald a poor prognosis.
Topics: Brain; Demyelinating Diseases; Hemorrhage; Humans; Magnetic Resonance Imaging; Multiple Sclerosis
PubMed: 35581949
DOI: 10.1177/13524585221094241