Microglia promote remyelination independent of their role in clearing myelin debris.

Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss. While therapies exist to slow MS progression, no treatment currently exists for remyelination. Remyelination, linked to reduced disability in MS, relies on microglia and monocyte-derived macrophages (MDMs).

Single-cell microglial transcriptomics during demyelination defines a microglial state required for lytic carcass clearance.

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.

The landscape of targets and lead molecules for remyelination.

Remyelination, or the restoration of myelin sheaths around axons in the central nervous system, is a multi-stage repair process that remains a major need for millions of patients with multiple sclerosis and other diseases of myelin. Even into adulthood, rodents and humans can generate new myelin-producing oligodendrocytes, leading to the therapeutic hypothesis that enhancing remyelination could lessen disease burden in multiple sclerosis. Multiple labs have used phenotypic screening to identify dozens of drugs that enhance oligodendrocyte formation, and several hit molecules have now advanced to clinical evaluation.

Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination.

The dietary consumption of cuprizone - a copper chelator - has long been known to induce demyelination of specific brain structures and is widely used as model of multiple sclerosis. Despite the extensive use of cuprizone, the mechanism by which it induces demyelination are still unknown. With this review we provide an updated understanding of this model, by showcasing two distinct yet overlapping modes of action for cuprizone-induced demyelination; 1) damage originating from within the oligodendrocyte, caused by mitochondrial dysfunction or reduced myelin protein synthesis.

Label-free assessment of myelin status using birefringence microscopy.

Background: Label-free methods for quantifying myelination can reduce expense, time, and variability in results when examining tissue white matter pathology.

New Method: We sought to determine whether the optical birefringent properties of myelin could be exploited to determine myelination status of white matter in tissue sections. Sections of forebrains of mice (normal, and treated with cuprizone to cause demyelination) were examined by birefringence using a birefringence imaging system (Thorlabs LCC7201), and results compared with sections stained using Luxol Fast Blue.

Nile Red fluorescence spectroscopy reports early physicochemical changes in myelin with high sensitivity.

The molecular composition of myelin membranes determines their structure and function. Even minute changes to the biochemical balance can have profound consequences for axonal conduction and the synchronicity of neural networks. Hypothesizing that the earliest indication of myelin injury involves changes in the composition and/or polarity of its constituent lipids, we developed a sensitive spectroscopic technique for defining the chemical polarity of myelin lipids in fixed frozen tissue sections from rodent and human.

Autofluorescence spectroscopy as a proxy for chronic white matter pathology.

Background: The balance of tissue injury and repair ultimately determines outcomes of chronic neurological disorders, such as progressive multiple sclerosis (MS). However, the extent of pathology can be difficult to detect, particularly when it is insidious and/or offset by tissue regeneration.

Objectives: The objective of this research is to evaluate whether tissue autofluorescence-typically a source of contamination-provides a surrogate marker of white matter injury.

Microglia response following acute demyelination is heterogeneous and limits infiltrating macrophage dispersion.

Microglia and infiltrating macrophages are thought to orchestrate the central nervous system (CNS) response to injury; however, the similarities between these cells make it challenging to distinguish their relative contributions. We genetically labeled microglia and CNS-associated macrophages to distinguish them from infiltrating macrophages. Using single-cell RNA sequencing, we describe multiple microglia activation states, one of which was enriched for interferon associated signaling.

Turned Inside Out: Will Myelin-Protective Therapies Become the Next-Generation Anti-Inflammatories?

The earliest and most proximal triggers of inflammatory demyelination in multiple sclerosis (MS) remain an open question. In this DNACB review we address experimental and clinical evidence consistent with subtle perturbations of the axo-myelinic compartment of central nervous system white matter as initiation sites of secondary autoimmune demyelination in MS. Strengthened by experimental evidence that by inhibiting myelinopathy one can prevent inflammatory demyelination, myelin-protective therapies may represent a new class of anti-inflammatory medications for combating myelin autoimmunity.

Development of a PET radioligand for potassium channels to image CNS demyelination.

Central nervous system (CNS) demyelination represents the pathological hallmark of multiple sclerosis (MS) and contributes to other neurological conditions. Quantitative and specific imaging of demyelination would thus provide critical clinical insight. Here, we investigated the possibility of targeting axonal potassium channels to image demyelination by positron emission tomography (PET).

Axo-myelinic neurotransmission: a novel mode of cell signalling in the central nervous system.

This corrects the article DOI: 10.1038/nrn.2017.

Axo-myelinic neurotransmission: a novel mode of cell signalling in the central nervous system.

It is widely recognized that myelination of axons greatly enhances the speed of signal transmission. An exciting new finding is the dynamic communication between axons and their myelin-forming oligodendrocytes, including activity-dependent signalling from axon to myelin. The oligodendrocyte-myelin complex may in turn respond by providing metabolic support or alter subtle myelin properties to modulate action potential propagation.

Mechanisms of lysophosphatidylcholine-induced demyelination: A primary lipid disrupting myelinopathy.

For decades lysophosphatidylcholine (LPC, lysolecithin) has been used to induce demyelination, without a clear understanding of its mechanisms. LPC is an endogenous lysophospholipid so it may cause demyelination in certain diseases. We investigated whether known receptor systems, inflammation or nonspecific lipid disruption mediates LPC-demyelination in mice.

Unique spectral signatures of the nucleic acid dye acridine orange can distinguish cell death by apoptosis and necroptosis.

Cellular injury and death are ubiquitous features of disease, yet tools to detect them are limited and insensitive to subtle pathological changes. Acridine orange (AO), a nucleic acid dye with unique spectral properties, enables real-time measurement of RNA and DNA as proxies for cell viability during exposure to various noxious stimuli. This tool illuminates spectral signatures unique to various modes of cell death, such as cells undergoing apoptosis versus necrosis/necroptosis.

Apoptosis of Oligodendrocytes during Early Development Delays Myelination and Impairs Subsequent Responses to Demyelination.

Unlabelled: During mammalian development, myelin-forming oligodendrocytes are generated and axons ensheathed according to a tightly regulated sequence of events. Excess premyelinating oligodendrocytes are eliminated by apoptosis and the timing of the onset of myelination in any specific CNS region is highly reproducible. Although the developing CNS recovers more effectively than the adult CNS from similar insults, it is unknown whether early loss of oligodendrocyte lineage cells leads to long-term functional deficits.

CNS myelin wrapping is driven by actin disassembly.

Myelin is essential in vertebrates for the rapid propagation of action potentials, but the molecular mechanisms driving its formation remain largely unknown. Here we show that the initial stage of process extension and axon ensheathment by oligodendrocytes requires dynamic actin filament assembly by the Arp2/3 complex. Unexpectedly, subsequent myelin wrapping coincides with the upregulation of actin disassembly proteins and rapid disassembly of the oligodendrocyte actin cytoskeleton and does not require Arp2/3.

Transcription factor-mediated reprogramming of fibroblasts to expandable, myelinogenic oligodendrocyte progenitor cells.

Cell-based therapies for myelin disorders, such as multiple sclerosis and leukodystrophies, require technologies to generate functional oligodendrocyte progenitor cells. Here we describe direct conversion of mouse embryonic and lung fibroblasts to induced oligodendrocyte progenitor cells (iOPCs) using sets of either eight or three defined transcription factors. iOPCs exhibit a bipolar morphology and global gene expression profile consistent with bona fide OPCs.

The PPARγ agonist pioglitazone crosses the blood-brain barrier and reduces tumor growth in a human xenograft model.

Purpose: The peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear hormone receptor family, represents a target in glioma therapy due to its antineoplastic effects in vitro on human glioma cell lines. We investigate the antineoplastic effects of the PPARγ agonist pioglitazone (pio) in a human glioma xenograft model to define the minimal required dose to induce antineoplastic effects. Additionally, we assess the ability of pio to cross the blood-brain barrier by measuring brain parenchymal concentration after oral administration.

Apoptosis of oligodendrocytes in the central nervous system results in rapid focal demyelination.

Objective: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that presents with variable pathologies that may reflect different disease-causing mechanisms. Existing animal models of MS induce pathology using either local injection of gliotoxins or stimulation of the immune system with myelin-related peptides. In none of these models is the primary cellular target well characterized, and although demyelination is a hallmark pathological feature in MS, it is unclear to what extent this reflects local oligodendrocyte loss.

Rapid and robust generation of functional oligodendrocyte progenitor cells from epiblast stem cells.

Myelin-related disorders such as multiple sclerosis and leukodystrophies, for which restoration of oligodendrocyte function would be an effective treatment, are poised to benefit greatly from stem cell biology. Progress in myelin repair has been constrained by difficulties in generating pure populations of oligodendrocyte progenitor cells (OPCs) in sufficient quantities. Pluripotent stem cells theoretically provide an unlimited source of OPCs, but current differentiation strategies are poorly reproducible and generate heterogenous populations of cells.

In vivo quantification of myelin changes in the vertebrate nervous system.

Destruction or changes associated with myelin membranes in the CNS play a key role in the pathogenesis of multiple sclerosis and other related neurodegenerative disorders. A long-standing goal has been to detect and quantify myelin content in vivo. For this reason, we have developed a myelin-imaging technique based on positron emission tomography (PET).

Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions.

Objective: To determine the role of bone morphogenetic proteins (BMPs) in stimulating glial scar formation in demyelinating lesions of the adult spinal cord.

Methods: The dorsal columns of adult rats were injected with lysolecithin to induce a local demyelinating lesion. Levels of BMP4 and BMP7 proteins were assayed and compared with glial fibrillary acidic protein expression in the injury area.