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BMJ Case Reports Mar 2020Young man with acute onset nausea, vomiting, joint pain, abdominal pain, fever and weight loss was found to have gait ataxia and positive titres. He deteriorated...
Young man with acute onset nausea, vomiting, joint pain, abdominal pain, fever and weight loss was found to have gait ataxia and positive titres. He deteriorated despite appropriate antibiotics and developed confusion and disorientation. Lumbar puncture revealed lymphocytosis with high protein and low glucose. MRI showed diffuse demyelination. Pulse steroids resulted in rapid clinical, biochemical and radiological recovery.
Topics: Adult; Anti-Bacterial Agents; Brain Diseases; Brucellosis; Demyelinating Diseases; Diagnosis, Differential; Drug Therapy, Combination; Glucocorticoids; Humans; Male; Methylprednisolone; Prednisolone
PubMed: 32152068
DOI: 10.1136/bcr-2019-233798 -
Arquivos de Neuro-psiquiatria Jul 2020
Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Neurocysticercosis
PubMed: 32725050
DOI: 10.1590/0004-282x20200034 -
Molecular Neurodegeneration Dec 2022Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia...
BACKGROUND
Microglia regulate the response to injury and disease in the brain and spinal cord. In white matter diseases microglia may cause demyelination. However, how microglia respond and regulate demyelination is not fully understood.
METHODS
To understand how microglia respond during demyelination, we fed mice cuprizone-a potent demyelinating agent-and assessed the dynamics of genetically fate-mapped microglia. We then used single-cell RNA sequencing to identify and track the microglial subpopulations that arise during demyelination. To understand how microglia contribute to the clearance of dead oligodendrocytes, we ablated microglia starting at the peak of cuprizone-induced cell death and used the viability dye acridine orange to monitor apoptotic and lytic cell morphologies after microglial ablation. Lastly, we treated serum-free primary microglial cultures to model distinct aspects of cuprizone-induced demyelination and assessed the response.
RESULTS
The cuprizone diet generated a robust microglial response by week 4 of the diet. Single-cell RNA sequencing at this time point revealed the presence of several cuprizone-associated microglia (CAM) clusters. These clusters expressed a transcriptomic signature indicative of cytokine regulation and reactive oxygen species production with altered lysosomal and metabolic changes consistent with ongoing phagocytosis. Using acridine orange to monitor apoptotic and lytic cell death after microglial ablation, we found that microglia preferentially phagocytose lytic carcasses. In culture, microglia exposed to lytic carcasses partially recapitulated the CAM state, suggesting that phagocytosis contributes to this distinct microglial state during cuprizone demyelination.
CONCLUSIONS
Microglia serve multiple roles during demyelination, yet their transcriptomic state resembles other neurodegenerative conditions. The phagocytosis of cellular debris is likely a universal cause for a common neurodegenerative microglial state.
Topics: Animals; Mice; Cuprizone; Microglia; Demyelinating Diseases; Transcriptome; Acridine Orange; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36514132
DOI: 10.1186/s13024-022-00584-2 -
Cells Apr 2021Myelin phagocytosis by macrophages has been an essential feature of demyelinating diseases in the central and peripheral nervous systems, including Guillain-Barré... (Review)
Review
Myelin phagocytosis by macrophages has been an essential feature of demyelinating diseases in the central and peripheral nervous systems, including Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multiple sclerosis (MS). The discovery of autoantibodies, including anti-ganglioside GM1 antibodies in the axonal form of GBS, anti-neurofascin 155 and anti-contactin 1 antibodies in typical and distal forms of CIDP, and anti-aquaporin 4 antibodies in neuromyelitis optica, contributed to the understanding of the disease process in a subpopulation of patients conventionally diagnosed with demyelinating diseases. However, patients with these antibodies are now considered to have independent disease entities, including acute motor axonal neuropathy, nodopathy or paranodopathy, and neuromyelitis optica spectrum disorder, because primary lesions in these diseases are distinct from those in conventional demyelinating diseases. Therefore, the mechanisms underlying demyelination caused by macrophages remain unclear. Electron microscopy studies revealed that macrophages destroy myelin as if they are the principal players in the demyelination process. Recent studies suggest that macrophages seem to select specific sites of myelinated fibers, including the nodes of Ranvier, paranodes, and internodes, for the initiation of demyelination in individual cases, indicating that specific components localized to these sites play an important role in the behavior of macrophages that initiate myelin phagocytosis. Along with the search for autoantibodies, the ultrastructural characterization of myelin phagocytosis by macrophages is a crucial step in understanding the pathophysiology of demyelinating diseases and for the future development of targeted therapies.
Topics: Animals; Autoantibodies; Demyelinating Diseases; Humans; Macrophages; Myelin Sheath
PubMed: 33917929
DOI: 10.3390/cells10040844 -
Acta Neuropathologica Communications Mar 2021Cognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains...
Cognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains and hippocampal atrophy correlates with cognitive decline in MS patients. Cellular and molecular mechanisms responsible for neuronal dysfunction in demyelinated hippocampi are not fully understood. Here we investigate a mouse model of hippocampal demyelination where twelve weeks of treatment with the oligodendrocyte toxin, cuprizone, demyelinates over 90% of the hippocampus and causes decreased memory/learning. Long-term potentiation (LTP) of hippocampal CA1 pyramidal neurons is considered to be a major cellular readout of learning and memory in the mammalian brain. In acute slices, we establish that hippocampal demyelination abolishes LTP and excitatory post-synaptic potentials of CA1 neurons, while pre-synaptic function of Schaeffer collateral fibers is preserved. Demyelination also reduced Ca-mediated firing of hippocampal neurons in vivo. Using three-dimensional electron microscopy, we investigated the number, shape (mushroom, stubby, thin), and post-synaptic densities (PSDs) of dendritic spines that facilitate LTP. Hippocampal demyelination did not alter the number of dendritic spines. Surprisingly, dendritic spines appeared to be more mature in demyelinated hippocampi, with a significant increase in mushroom-shaped spines, more perforated PSDs, and more astrocyte participation in the tripartite synapse. RNA sequencing experiments identified 400 altered transcripts in demyelinated hippocampi. Gene transcripts that regulate myelination, synaptic signaling, astrocyte function, and innate immunity were altered in demyelinated hippocampi. Hippocampal remyelination rescued synaptic transmission, LTP, and the majority of gene transcript changes. We establish that CA1 neurons projecting demyelinated axons silence their dendritic spines and hibernate in a state that may protect the demyelinated axon and facilitates functional recovery following remyelination.
Topics: Animals; Astrocytes; Cognitive Dysfunction; Cuprizone; Demyelinating Diseases; Dendritic Spines; Disease Models, Animal; Hippocampus; Long-Term Potentiation; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Microscopy, Electron; Multiple Sclerosis; Neurons; Post-Synaptic Density; Sequence Analysis, RNA
PubMed: 33648591
DOI: 10.1186/s40478-021-01130-9 -
Clinical Immunology (Orlando, Fla.) Apr 2018Infection of the central nervous system (CNS) by neurotropic viruses represents an increasing worldwide problem in terms of morbidity and mortality for people of all... (Review)
Review
Infection of the central nervous system (CNS) by neurotropic viruses represents an increasing worldwide problem in terms of morbidity and mortality for people of all ages. Although unique structural features of the blood-brain-barrier (BBB) provide a physical and physiological barrier, a number of neurotropic viruses are able to enter the CNS resulting in a variety of pathological outcomes. Nonetheless, antigen-specific lymphocytes are ultimately able to accumulate within the CNS and contribute to defense by reducing or eliminating the invading viral pathogen. Alternatively, infiltration of activated cells of the immune system may be detrimental, as these cells can contribute to neuropathology that may result in long-term cellular damage or death. More recently, myeloid cells e.g. neutrophils have been implicated in contributing to both host defense and disease in response to viral infection of the CNS. This review highlights recent studies using coronavirus-induced neurologic disease as a model to determine how neutrophils affect effective control of viral replication as well as demyelination.
Topics: Animals; Blood-Brain Barrier; Coronavirus; Coronavirus Infections; Demyelinating Diseases; Humans; Immune System; Nervous System Diseases; Neutrophils; T-Lymphocytes
PubMed: 27288312
DOI: 10.1016/j.clim.2016.05.009 -
Glia Oct 2020The presence of peripheral myelinating cells in the central nervous system (CNS) has gained the neurobiologist attention over the years. Despite the confirmed presence... (Review)
Review
The presence of peripheral myelinating cells in the central nervous system (CNS) has gained the neurobiologist attention over the years. Despite the confirmed presence of Schwann cells in the CNS in pathological conditions, and the long list of their beneficial effects on central remyelination, the cues that impede or allow Schwann cells to successfully conquer and remyelinate central axons remain partially undiscovered. A better knowledge of these factors stands out as crucial to foresee a rational therapeutic approach for the use of Schwann cells in CNS repair. Here, we review the diverse origins of Schwann cells into the CNS, both peripheral and central, as well as the CNS components that inhibit Schwann survival and migration into the central parenchyma. Namely, we analyze the astrocyte- and the myelin-derived components that restrict Schwann cells into the CNS. Finally, we highlight the unveiled mode of invasion of these peripheral cells through the central environment, using blood vessels as scaffolds to pave their ways toward demyelinated lesions. In short, this review presents the so far uncovered knowledge of this complex CNS-peripheral nervous system (PNS) relationship.
Topics: Animals; Cell Movement; Cell Survival; Central Nervous System; Demyelinating Diseases; Humans; Myelin Sheath; Peripheral Nervous System; Remyelination; Schwann Cells
PubMed: 32027054
DOI: 10.1002/glia.23788 -
Acta Neuropathologica Communications Nov 2018Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by massive infiltration of immune cells, demyelination, and axonal loss. Active... (Review)
Review
Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by massive infiltration of immune cells, demyelination, and axonal loss. Active MS lesions mainly consist of macrophages and microglia containing abundant intracellular myelin remnants. Initial studies showed that these foamy phagocytes primarily promote MS disease progression by internalizing myelin debris, presenting brain-derived autoantigens, and adopting an inflammatory phenotype. However, more recent studies indicate that phagocytes can also adopt a beneficial phenotype upon myelin internalization. In this review, we summarize and discuss the current knowledge on the spatiotemporal physiology of foamy phagocytes in MS lesions, and elaborate on extrinsic and intrinsic factors regulating their behavior. In addition, we discuss and link the physiology of myelin-containing phagocytes to that of foamy macrophages in other disorders such atherosclerosis.
Topics: Animals; Demyelinating Diseases; Humans; Macrophages; Microglia; Multiple Sclerosis; Myelin Sheath; Phagocytes
PubMed: 30454040
DOI: 10.1186/s40478-018-0628-8 -
Cells Mar 2020Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Various pre-clinical models with different specific features of... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Various pre-clinical models with different specific features of the disease are available to study MS pathogenesis and to develop new therapeutic options. During the last decade, the model of toxic demyelination induced by cuprizone has become more and more popular, and it has contributed substantially to our understanding of distinct yet important aspects of the MS pathology. Here, we aim to provide a practical guide on how to use the cuprizone model and which pitfalls should be avoided.
Topics: Animals; Body Weight; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Gene Expression Regulation; Multiple Sclerosis
PubMed: 32244377
DOI: 10.3390/cells9040843 -
Pflugers Archiv : European Journal of... Dec 2022The cuprizone model is a widely used model to study the pathogenesis of multiple sclerosis (MS). Due to the selective loss of mature oligodendrocytes and myelin, it is...
The cuprizone model is a widely used model to study the pathogenesis of multiple sclerosis (MS). Due to the selective loss of mature oligodendrocytes and myelin, it is mainly being used to study demyelination and the mechanisms of remyelination, as well as the efficiency of compounds or therapeutics aiming at remyelination. Although early investigations using high dosages of cuprizone reported the occurrence of hydrocephalus, it has long been assumed that cuprizone feeding at lower dosages does not induce changes at the blood-brain barrier (BBB). Here, by analyzing BBB ultrastructure with high-resolution electron microscopy, we report changes at astrocytic endfeet surrounding vessels in the brain parenchyma. Particularly, edema formation around blood vessels and swollen astrocytic endfeet already occurred after feeding low dosages of cuprizone. These findings indicate changes in BBB function that will have an impact on the milieu of the central nervous system (CNS) in the cuprizone model and need to be considered when studying the mechanisms of de- and remyelination.
Topics: Animals; Mice; Cuprizone; Astrocytes; Demyelinating Diseases; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36241864
DOI: 10.1007/s00424-022-02759-8