Disruption of the BBB is critical to initiation and perpetuation of disease in Multiple Sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration. Perivascular OPCs can themselves disrupt the BBB, interfering with astrocyte end-feet and endothelial tight junction integrity, resulting in altered vascular permeability and an associated CNS inflammation. Aberrant Wnt tone in OPCs mediates their dysfunctional vascular detachment, and also leads to OPC secretion of Wif1, that interferes with Wnt ligand function on endothelial tight junction integrity. Evidence for this defective oligodendroglial-vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB.

Oligodendrocyte precursor cells (OPCs) undergo a series of energyconsuming developmental events; however, the uptake and trafficking pathways for their energy metabolites remain unknown. In the present study, we found that 2-NBDG, a fluorescent glucose analog, can be delivered between astrocytes and oligodendrocytes through connexin-based gap junction channels but cannot be transferred between astrocytes and OPCs. Instead, connexin hemichannel-mediated glucose uptake supports OPC proliferation, and ethidium bromide uptake or increase of 2-NBDG uptake rate is correlated with intracellular Ca 2+ elevation in OPCs, indicating a Ca 2+ -dependent activation of connexin hemichannels. Interestingly, deletion of connexin 43 (Cx43, also known as GJA1) in astrocytes inhibits OPC proliferation by decreasing matrix glucose levels without impacting on OPC hemichannel properties, a process that also occurs in corpus callosum from acute brain slices. Thus, dual functions of connexin-based channels contribute to glucose supply in oligodendroglial lineage, which might pave a new way for energymetabolism-directed oligodendroglial-targeted therapies.

As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs. Our data demonstrated that (i) QUE monotherapy can effectively suppress GSCs-initiated tumor growth; (ii) QUE has synergistic effects with temozolomide (TMZ) on glioma suppression, and importantly, QUE can effectively suppress TMZ-resistant (or -escaped) tumors generated from GSCs; (iii) mechanistically, the anti-glioma effect of QUE was due to its actions of promoting the differentiation of GSCs into oligodendrocyte (OL)-like cells and its inhibitory effect on the Wnt/β-catenin signaling pathway. Together, our findings suggest an effective approach for anti-gliomagenic treatment via targeting OL-oriented differentiation of GSCs. This also opens a door for repurposing QUE, an FDA approved drug, for the treatment of malignant glioma.

No abstract

Autism spectrum disorder (ASD) is the most commonly diagnosed neurodevelopmental disorder. Independent of neuronal dysfunction, ASD and its associated comorbidities have been linked to hypomyelination and oligodendroglial dysfunction. Additionally, the neuromodulator adenosine has been shown to affect certain ASD comorbidities and symptoms, such as epilepsy, impairment of cognitive function, and anxiety. Adenosine is both directly and indirectly responsible for regulating the development of oligodendroglia and myelination through its interaction with, and modulation of, several neurotransmitters, including glutamate, dopamine, and serotonin. In this review, we will focus on the recent discoveries in adenosine interaction with physiological and pathophysiological activities of oligodendroglia and myelination, as well as ASD-related aspects of adenosine actions on neuroprotection and neuroinflammation. Moreover, we will discuss the potential therapeutic value and clinical approaches of adenosine manipulation against hypomyelination in ASD.

Aspirin, one of the most commonly used anti-inflammatory drugs, has been recently reported to display multiple effects in the central nervous system (CNS), including neuroprotection and upregulation of ciliary neurotrophic factor (CNTF) expression in astrocytes. Although it was most recently reported that aspirin could promote the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) after white matter lesion, the underlying mechanisms remain unclear. To dissect the effects of aspirin on oligodendroglial development and explore possible mechanisms, we here demonstrated the following: (i) in vitro treatment of aspirin on OPC cultures significantly increased the number of differentiated oligodendrocytes (OLs) but had no effect on the number of proliferative OPCs, indicating that aspirin can promote OPC differentiation but not proliferation; (ii) in vivo treatment of aspirin on neonatal (P3) rats for 4 days led to a nearly twofold increase in the expression of myelin basic protein (MBP), devoid of change in OPC proliferaion, in the corpus callosum (CC); (iii) finally, aspirin treatment increased the phosphorylation level of β-catenin and counteracted Wnt signaling pathway synergist QS11-induced suppression on OPC differentiation. Together, our data show that aspirin can directly target oligodendroglial lineage cells and promote their differentiation through inhibition of Wnt/β-catenin signaling pathway. These findings suggest that aspirin may be a novel candidate for the treatment of demyelinating diseases.

Aging affects almost all the aspects of brain functions, but the mechanisms remain largely undefined. Increasing number of literatures have manifested the important role of glial cells in regulating the aging process. Oligodendroglial lineage cell is a major type of glia in central nervous system (CNS), composed of mature oligodendrocytes (OLs), and oligodendroglia precursor cells (OPCs). OLs produce myelin sheaths that insulate axons and provide metabolic support to meet the energy demand. OPCs maintain the population throughout lifetime with the abilities to proliferate and differentiate into OLs. Increasing evidence has shown that oligodendroglial cells display active dynamics in adult and aging CNS, which is extensively involved in age-related brain function decline in the elderly. In this review, we summarized present knowledge about dynamic changes of oligodendroglial lineage cells during normal aging and discussed their potential roles in age-related functional decline. Especially, focused on declined myelinogenesis during aging and underlying mechanisms. Clarifying those oligodendroglial changes and their effects on neurofunctional decline may provide new insights in understanding aging associated brain function declines.

Myelinating glial cells (MGCs), oligodendrocytes (OLs) in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS), generate myelin sheaths that insulate axons. After myelination is completed in adulthood, MGC functions independent from myelin are required to support axon survival, but the underlying mechanisms are still unclear. Dicer is a key enzyme that is responsible for generating functional micro-RNAs (miRNAs). Despite the importance of Dicer in initiating myelination, the role of Dicer in mature MGCs is still unclear. Here, Dicer was specifically deleted in mature MGCs in 2-month old mice (PLP-CreERT; Dicer fl/fl) by tamoxifen administration. Progressive motor dysfunction was observed in the Dicer conditional knockout mice, which displayed hind limb ataxia at 3 months post recombination that deteriorated into paralysis within 5 months. Massive axonal degeneration/atrophy in peripheral nerves was responsible for this phenomenon, but overt demyelination was not observed in either the CNS or PNS. In contrast to the PNS, signs of axonal degeneration were not observed in the CNS of these animals. We induced a Dicer deletion in oligodendroglia at postnatal day 5 in NG2-CreERT; Dicer fl/fl mice to evaluate whether Dicer expression in OLs is essential for axonal survival. Dicer deletion in oligodendroglia did not cause motor dysfunction at the age of 7 months. Neither axonal atrophy nor demyelination was observed in the CNS. Based on our results, Dicer expression in SCs is required to maintain axon integrity in adult PNS, and Dicer is dispensable for maintaining myelin sheaths in MGCs.