Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age.

The aging brain is associated with significant changes in physiology that alter the tissue microenvironment of the central nervous system (CNS). In the aged CNS, increased demyelination has been associated with astrocyte hypertrophy and aging has been implicated as a basis for these pathological changes. Aging tissues accumulate chronic cellular stress, which can lead to the development of a pro-inflammatory phenotype that can be associated with cellular senescence. Herein, we provide evidence that astrocytes aged in culture develop a spontaneous pro-inflammatory and senescence-like phenotype. We found that extracellular vesicles (EVs) from young astrocyte were sufficient to convey support for oligodendrocyte differentiation while this support was lost by EVs from aged astrocytes. Importantly, the negative influence of culture age on astrocytes, and their cognate EVs, could be countered by treatment with rapamycin. Comparative proteomic analysis of EVs from young and aged astrocytes revealed peptide repertoires unique to each age. Taken together, these findings provide new information on the contribution of EVs as potent mediators by which astrocytes can extert changing influence in either the disease or aged brain

Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age

Abstract: The aging brain is associated with significant changes in physiology that alter the tissue microenvironment of the central nervous system (CNS). In the aged CNS, increased demyelination has been associated with astrocyte hypertrophy and aging has been implicated as a basis for these pathological changes. Aging tissues accumulate chronic cellular stress, which can lead to the development of a pro-inflammatory phenotype that can be associated with cellular senescence. Herein, we provide evidence that astrocytes aged in culture develop a spontaneous pro-inflammatory and senescence-like phenotype. We found that extracellular vesicles (EVs) from young astrocyte were sufficient to convey support for oligodendrocyte differentiation while this support was lost by EVs from aged astrocytes. Importantly, the negative influence of culture age on astrocytes, and their cognate EVs, could be countered by treatment with rapamycin. Comparative proteomic analysis of EVs from young and aged astrocytes revealed peptide repertoires unique to each age. Taken together, these findings provide new information on the contribution of EVs as potent mediators by which astrocytes can extert changing influence in either the disease or aged brain

microRNA-219 Reduces Viral Load and Pathologic Changes in Theiler's Virus-Induced Demyelinating Disease

Analysis of microRNA (miR) expression in the central nervous system white matter of SJL mice infected with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) revealed a significant reduction of miR-219, a critical regulator of myelin assembly and repair. Restoration of miR-219 expression by intranasal administration of a synthetic miR-219 mimic before disease onset ameliorates clinical disease, reduces neurogliosis, and partially recovers motor and sensorimotor function by negatively regulating proinflammatory cytokines and virus RNA replication. Moreover, RNA sequencing of host lesions showed that miR-219 significantly downregulated two genes essential for the biosynthetic cholesterol pathway, Cyp51 (lanosterol 14-α-demethylase) and Srebf1 (sterol regulatory element-binding protein-1), and reduced cholesterol biosynthesis in infected mice and rat CG-4 glial precursor cells in culture. The change in cholesterol biosynthesis had both anti-inflammatory and anti-viral effects. Because RNA viruses hijack endoplasmic reticulum double-layered membranes to provide a platform for RNA virus replication and are dependent on endogenous pools of cholesterol, miR-219 interference with cholesterol biosynthesis interfered virus RNA replication. These findings demonstrate that miR-219 inhibits TMEV-induced demyelinating disease through its anti-inflammatory and anti-viral properties. MicroRNAs (miRs) are small noncoding RNAs that regulate a myriad of biological processes by controlling gene expression. In the latest issue of Molecular Therapy, Moyano et al. show that intranasal delivery of miR-219 in a mouse model of viral demyelination reduces neurological burden and improves life quality through anti-inflammatory and anti-viral mechanisms.Fil: Moyano, Ana Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; Argentina. University of Illinois; Estados UnidosFil: Steplowski, Jeffrey. University of Illinois; Estados UnidosFil: Wang, Haibo. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Son, Kyung No. University of Illinois; Estados UnidosFil: Rapolti, Diana I.. University of Illinois; Estados UnidosFil: Marshall, Jeffrey. University of Illinois; Estados UnidosFil: Elackattu, Vince. University of Illinois; Estados UnidosFil: Marshall, Michael S.. University of Illinois; Estados UnidosFil: Hebert, Amy K.. University of Illinois; Estados UnidosFil: Reiter, Cory R.. University of Illinois; Estados UnidosFil: Ulloa, Viviana. University of Illinois; Estados UnidosFil: Pituch, Katarzyna C.. University of Illinois; Estados UnidosFil: Givogri, Maria I.. University of Illinois; Estados UnidosFil: Lu, Q. Richard. Cincinnati Children's Hospital Medical Center; Estados UnidosFil: Lipton, Howard L.. University of Illinois; Estados UnidosFil: Bongarzone, Ernesto R.. University of Illinois; Estados Unidos. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentin

Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age.

The aging brain is associated with significant changes in physiology that alter the tissue microenvironment of the central nervous system (CNS). In the aged CNS, increased demyelination has been associated with astrocyte hypertrophy and aging has been implicated as a basis for these pathological changes. Aging tissues accumulate chronic cellular stress, which can lead to the development of a pro-inflammatory phenotype that can be associated with cellular senescence. Herein, we provide evidence that astrocytes aged in culture develop a spontaneous pro-inflammatory and senescence-like phenotype. We found that extracellular vesicles (EVs) from young astrocyte were sufficient to convey support for oligodendrocyte differentiation while this support was lost by EVs from aged astrocytes. Importantly, the negative influence of culture age on astrocytes, and their cognate EVs, could be countered by treatment with rapamycin. Comparative proteomic analysis of EVs from young and aged astrocytes revealed peptide repertoires unique to each age. Taken together, these findings provide new information on the contribution of EVs as potent mediators by which astrocytes can extert changing influence in either the disease or aged brain

Astrocyte Support for Oligodendrocyte Differentiation can be Conveyed via Extracellular Vesicles but Diminishes with Age

Abstract: The aging brain is associated with significant changes in physiology that alter the tissue microenvironment of the central nervous system (CNS). In the aged CNS, increased demyelination has been associated with astrocyte hypertrophy and aging has been implicated as a basis for these pathological changes. Aging tissues accumulate chronic cellular stress, which can lead to the development of a pro-inflammatory phenotype that can be associated with cellular senescence. Herein, we provide evidence that astrocytes aged in culture develop a spontaneous pro-inflammatory and senescence-like phenotype. We found that extracellular vesicles (EVs) from young astrocyte were sufficient to convey support for oligodendrocyte differentiation while this support was lost by EVs from aged astrocytes. Importantly, the negative influence of culture age on astrocytes, and their cognate EVs, could be countered by treatment with rapamycin. Comparative proteomic analysis of EVs from young and aged astrocytes revealed peptide repertoires unique to each age. Taken together, these findings provide new information on the contribution of EVs as potent mediators by which astrocytes can extert changing influence in either the disease or aged brain

Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe’s disease

<div><p>In prior studies, our laboratory showed that psychosine accumulates and disrupts lipid rafts in brain membranes of Krabbe’s disease. A model of lipid raft disruption helped explaining psychosine’s effects on several signaling pathways important for oligodendrocyte survival and differentiation but provided more limited insight in how this sphingolipid caused demyelination. Here, we have studied how this cationic inverted coned lipid affects the fluidity, stability and structure of myelin and plasma membranes. Using a combination of cutting-edge imaging techniques in non-myelinating (red blood cell), and myelinating (oligodendrocyte) cell models, we show that psychosine is sufficient to disrupt sphingomyelin-enriched domains, increases the rigidity of localized areas in the plasma membrane, and promotes the shedding of membranous microvesicles. The same physicochemical and structural changes were measured in myelin membranes purified from the mutant mouse Twitcher, a model for Krabbe’s disease. Areas of higher rigidity were measured in Twitcher myelin and correlated with higher levels of psychosine and of myelin microvesiculation. These results expand our previous analyses and support, for the first time a pathogenic mechanism where psychosine’s toxicity in Krabbe disease involves deregulation of cell signaling not only by disruption of membrane rafts, but also by direct local destabilization and fragmentation of the membrane through microvesiculation. This model of membrane disruption may be fundamental to introduce focal weak points in the myelin sheath, and consequent diffuse demyelination in this leukodystrophy, with possible commonality to other demyelinating disorders.</p></div

Psychosine increases rigidity in focalized areas of the RBC plasma membrane.

<p><b>A-C)</b> Overall fluidity in RBCs (<b>A,B</b>) and purified P40 brain myelin (<b>C</b>) measured by TMA-DPH is not affected by psychosine or in Twitcher mice. Wild-type, Twitcher, and wild-type RBCs preincubated with increasing concentrations of psychosine were analyzed by TMA-DPH anisotropy. <b>D-H)</b> Multiphoton excitation microscopy imaging of Laurdan in P40 wild-type (<b>D</b>), Twitcher (<b>E</b>), and wild-type RBCs treated with 2 (<b>F</b>), 5 (<b>G</b>) or 10 μM of psychosine for 30 minutes at 37^°C. (<b>H</b>). GP images are in pseudo-colors with the range indicated by the color bar going from fluid (blue/green) to rigid (yellow/red). Scale bar, 10 μm. <b>I)</b> GP value from the center of RBCs were analyzed as represented inside the white dashed circles in (<b>D</b>) and plotted as % of change from wild-type values. <b>J</b>) Distribution of domains of high GP and high-rigidity. Results are mean ± SEM of samples N = 68–257 in 3–4 independent experiments. NS, not significant (>0.05); *, <i>p</i> <0.05; **, <i>p</i> <0.01; ***, <i>p</i> <0.001.</p

Psychosine reduces sphingomyelin and cholesterol lateral mobility.

<p>Psychosine reduces sphingomyelin and cholesterol lateral mobility.</p