Cerebellar white matter development is regulated by fractalkine-dependent microglia phagocytosis of oligodendrocyte progenitor cells.

Unlabelled: Complex neurodevelopmental disorders involve motor as well as cognitive dysfunction and these impairments are associated with both cerebral and cerebellar maturity. A network of connections between these two brain regions is proposed to underlie neurodevelopmental impairments. The cerebellar gray matter has a protracted developmental timeline compared to the cerebral cortex, however, making the association of these relay pathways unclear for neurodevelopmental disabilities.

Inhibiting AMPA receptor signaling in oligodendrocytes rescues synapse loss in a model of autoimmune demyelination.

Multiple sclerosis (MS) is initially characterized by myelin and axonal damage in central nervous system white matter lesions, but their causal role in synapse loss remains undefined. Gray matter atrophy is also present early in MS, making it unclear if synaptic alterations are driven by white matter demyelinating lesions or primary gray matter damage. Furthermore, whether axonal pathology occurs secondary to or independent of demyelination to drive synaptic changes is not clear.

Utility of the visual system to monitor neurodegeneration in multiple sclerosis.

Neurodegeneration occurs early in the multiple sclerosis (MS) disease course and is an important driver of permanent disability. Current immunomodulatory therapies do not directly target neuronal health; thus, there is a critical need to develop neuroprotective strategies in MS. Outcome measures in clinical trials primarily evaluate disease activity and clinical disability scores rather than measures of neurodegeneration.

Hyperoxia Induced Hypomyelination.

We asked whether hyperoxia might induce hypomyelination of the corpus callosum, clinically described as periventricular leukomalacia (PVL) of the severely preterm infant. Mouse pups and their nursing dams were placed in 80% oxygen from P4-P8, then removed to room air until P11. Corpus callosal sections were probed myelin immunofluorescence, tested for myelin basic protein concentration by Western blot, and both glial fibrillary acidic protein levels and apoptosis quantified.

Endothelial-to-mesenchymal transition in multiple sclerosis: Good cells gone bad.

In cancer and cardiovascular disease, endothelial cells can transform into mesenchymal cells (EndoMT), affecting disease onset and progression. In this issue of Neuron, Sun et al. (2022) demonstrate how EndoMT triggers breakdown of the blood-CNS barrier in the pathogenesis of multiple sclerosis.

Remyelinating strategies: What can be learned from normal brain development.

Multiple sclerosis (MS) is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Immunomodulatory therapies are effective in reducing relapses, however, there is no remedy for progressive disease emphasizing the need for regenerative strategies. Chronic demyelination causes axonal injury and loss which is a key component of neurodegeneration and permanent disability in MS.

Neurodegeneration in multiple sclerosis.

Axonal loss in multiple sclerosis (MS) is a key component of disease progression and permanent neurologic disability. MS is a heterogeneous demyelinating and neurodegenerative disease of the central nervous system (CNS) with varying presentation, disease courses, and prognosis. Immunomodulatory therapies reduce the frequency and severity of inflammatory demyelinating events that are a hallmark of MS, but there is minimal therapy to treat progressive disease and there is no cure.

Visual imaging as a predictor of neurodegeneration in experimental autoimmune demyelination and multiple sclerosis.

Thalamic volume is associated with clinical disability in multiple sclerosis (MS) and is vulnerable to secondary neurodegeneration due to its extensive connectivity throughout the central nervous system (CNS). Using a model of autoimmune demyelination that exhibits CNS-infiltrating immune cells in both spinal cord white matter and optic nerve, we sought to evaluate neurodegenerative changes due to lesions affecting the spino- and retino-thalamic pathways. We found comparable axonal loss in spinal cord white matter and optic nerve during the acute phase of disease consistent with synaptic loss, but not neuronal cell body loss in the thalamic nuclei that receive input from these discrete pathways.

Peripheral sTREM2-Related Inflammatory Activity Alterations in Early-Stage Alzheimer's Disease.

Alzheimer's disease (AD) has been linked to multiple immune system-related genetic variants. Triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. In addition, soluble TREM2 (sTREM2) isoform is elevated in cerebrospinal fluid in the early stages of AD and is associated with slower cognitive decline in a disease stage-dependent manner.

Microglia phagocytose oligodendrocyte progenitor cells and synapses during early postnatal development: implications for white versus gray matter maturation.

Emerging roles for microglia in modifying normal brain development continue to provide new perspectives on the functions of this resident immune cell in the brain. While the molecular underpinnings driving microglia's position in regulating developmental programs remain largely an unchartered territory, innate immune signaling lies at the forefront. At least three innate immune receptors expressed on microglia-fractalkine, complement, and triggering receptor expressed on microglia (TREM2)-modulate developmental synaptic pruning to refine brain circuitry.

Quantification of microglial contact and engulfment of oligodendrocyte progenitor cells in the rodent brain.

Microglia have emerged as essential regulators of neurodevelopment by phagocytosing synapses. Recently, we showed that microglia engulf viable oligodendrocyte progenitor cells (OPCs) during development to facilitate myelination. Here, we describe a protocol to quantify microglial engulfment of whole cells using 3D confocal microscopy to differentiate microglial contact.

Lupus-prone B6.Nba2 male and female mice display anti-DWEYS reactivity and a neuropsychiatric phenotype.

Objective: Neuropsychiatric lupus (NPSLE), a manifestation of the autoimmune disease systemic lupus erythematosus (SLE), is characterized by psychiatric symptoms including anxiety and depression and upregulated autoantibodies. The B6.Nba2 spontaneous mouse model develops SLE, but has not previously been tested for NPSLE.

Fractalkine-Dependent Microglial Pruning of Viable Oligodendrocyte Progenitor Cells Regulates Myelination.

Oligodendrogenesis occurs during early postnatal development, coincident with neurogenesis and synaptogenesis, raising the possibility that microglia-dependent pruning mechanisms that modulate neurons regulate myelin sheath formation. Here we show a population of ameboid microglia migrating from the ventricular zone into the corpus callosum during early postnatal development, termed "the fountain of microglia," phagocytosing viable oligodendrocyte progenitor cells (OPCs) before onset of myelination. Fractalkine receptor-deficient mice exhibit a reduction in microglial engulfment of viable OPCs, increased numbers of oligodendrocytes, and reduced myelin thickness but no change in axon number.

Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflammation.

Glutamate dysregulation occurs in multiple sclerosis (MS), but whether excitotoxic mechanisms in mature oligodendrocytes contribute to demyelination and axonal injury is unexplored. Although current treatments modulate the immune system, long-term disability ensues, highlighting the need for neuroprotection. Glutamate is elevated before T2-visible white matter lesions appear in MS.

Treg-specific IL-27Rα deletion uncovers a key role for IL-27 in Treg function to control autoimmunity.

Dysregulated Foxp3 Treg functions result in uncontrolled immune activation and autoimmunity. Therefore, identifying cellular factors modulating Treg functions is an area of great importance. Here, using Treg-specific mice, we report that IL-27 signaling in Foxp3 Tregs is essential for Tregs to control autoimmune inflammation in the central nervous system (CNS).

Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination.

A major hallmark of the autoimmune demyelinating disease multiple sclerosis (MS) is immune cell infiltration into the brain and spinal cord resulting in myelin destruction, which not only slows conduction of nerve impulses, but causes axonal injury resulting in motor and cognitive decline. Current treatments for MS focus on attenuating immune cell infiltration into the central nervous system (CNS). These treatments decrease the number of relapses, improving quality of life, but do not completely eliminate relapses so long-term disability is not improved.

Myocardial ischemia/reperfusion impairs neurogenesis and hippocampal-dependent learning and memory.

The incidence of cognitive impairment in cardiovascular disease (CVD) patients has increased, adversely impacting quality of life and imposing a significant economic burden. Brain imaging of CVD patients has detected changes in the hippocampus, a brain region critical for normal learning and memory. However, it is not clear whether adverse cardiac events or other associated co-morbidities impair cognition.

T cell cytokine signatures: Biomarkers in pediatric multiple sclerosis.

Although multiple sclerosis is predominantly regarded as a disease of young adulthood, up to 5% of MS patients are diagnosed prior to age eighteen. The predominant form of MS is relapsing-remitting characterized by exacerbations of symptoms followed by periods of remission. The majority of disease modifying drugs target T cell proliferation or block migration into the central nervous system.

Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination.

T cell infiltration into the CNS is a significant underlying pathogenesis in autoimmune inflammatory demyelinating diseases. Several lines of evidence suggest that glutamate dysregulation in the CNS is an important consequence of immune cell infiltration in neuroinflammatory demyelinating diseases; yet, the causal link between inflammation and glutamate dysregulation is not well understood. A major source of glutamate release during oxidative stress is the system Xc(-) transporter; however, this mechanism has not been tested in animal models of autoimmune inflammatory demyelination.

Expression of EAAT2 in neurons and protoplasmic astrocytes during human cortical development.

The major regulators of synaptic glutamate in the cerebral cortex are the excitatory amino acid transporters 1-3 (EAAT1-3). In this study, we determined the cellular and temporal expression of EAAT1-3 in the developing human cerebral cortex. We applied single- and double-label immunocytochemistry to normative frontal or parietal (associative) cortex samples from 14 cases ranging in age from 23 gestational weeks to 2.