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1.
Nat Neurosci ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38816530

RESUMO

Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4-24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects in activity-dependent oligodendrogenesis and harbor focal OPC hyperdensities with disrupted homeostatic OPC territorial boundaries. These OPC hyperdensities develop in a cell-intrinsic Nf1 mutation-specific manner due to differential PI3K/AKT activation. OPC-specific Nf1 loss impairs oligodendroglial differentiation and abrogates the normal oligodendroglial response to neuronal activity, leading to impaired motor learning performance. Collectively, these findings show that Nf1 mutation delays oligodendroglial development and disrupts activity-dependent OPC function essential for normal motor learning in mice.

2.
Immunity ; 56(9): 2105-2120.e13, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37527657

RESUMO

Childhood neglect and/or abuse can induce mental health conditions with unknown mechanisms. Here, we identified stress hormones as strong inducers of astrocyte-mediated synapse phagocytosis. Using in vitro, in vivo, and human brain organoid experiments, we showed that stress hormones increased the expression of the Mertk phagocytic receptor in astrocytes through glucocorticoid receptor (GR). In post-natal mice, exposure to early social deprivation (ESD) specifically activated the GR-MERTK pathway in astrocytes, but not in microglia. The excitatory post-synaptic density in cortical regions was reduced in ESD mice, and there was an increase in the astrocytic engulfment of these synapses. The loss of excitatory synapses, abnormal neuronal network activities, and behavioral abnormalities in ESD mice were largely prevented by ablating GR or MERTK in astrocytes. Our work reveals the critical roles of astrocytic GR-MERTK activation in evoking stress-induced abnormal behaviors in mice, suggesting GR-MERTK signaling as a therapeutic target for stress-induced mental health conditions.


Assuntos
Astrócitos , Fagocitose , Estresse Psicológico , Animais , Criança , Humanos , Camundongos , Astrócitos/metabolismo , c-Mer Tirosina Quinase/genética , Hormônios/metabolismo , Sinapses/metabolismo , Estresse Psicológico/metabolismo
3.
Mol Ther ; 31(4): 1002-1016, 2023 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-36755495

RESUMO

Fabry disease (FD), a lysosomal storage disorder, is caused by defective α-galactosidase (GLA) activity, which results in the accumulation of globotriaosylceramide (Gb3) in endothelial cells and leads to life-threatening complications such as left ventricular hypertrophy (LVH), renal failure, and stroke. Enzyme replacement therapy (ERT) results in Gb3 clearance; however, because of a short half-life in the body and the high immunogenicity of FD patients, ERT has a limited therapeutic effect, particularly in patients with late-onset disease or progressive complications. Because vascular endothelial cells (VECs) derived from FD-induced pluripotent stem cells display increased thrombospondin-1 (TSP1) expression and enhanced SMAD2 signaling, we screened for chemical compounds that could downregulate TSP1 and SMAD2 signaling. Fasudil reduced the levels of p-SMAD2 and TSP1 in FD-VECs and increased the expression of angiogenic factors. Furthermore, fasudil downregulated the endothelial-to-mesenchymal transition (EndMT) and mitochondrial function of FD-VECs. Oral administration of fasudil to FD mice alleviated several FD phenotypes, including LVH, renal fibrosis, anhidrosis, and heat insensitivity. Our findings demonstrate that fasudil is a novel candidate for FD therapy.


Assuntos
Doença de Fabry , Animais , Camundongos , Doença de Fabry/tratamento farmacológico , Doença de Fabry/genética , Células Endoteliais/metabolismo , alfa-Galactosidase/genética , Fenótipo , Terapia de Reposição de Enzimas
4.
Methods Mol Biol ; 1938: 155-168, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30617979

RESUMO

Astrocytes eliminate unnecessary synapses, neural debris, and pathogenic proteins such as amyloid ß plaque. Although the emerging evidences suggest that the phagocytic roles of astrocytes are critical in maintaining brain homeostasis during development as well as pathogenic conditions, the efficient assay for measuring phagocytic capacity and kinetics of astrocytes has been lacking. Here we present in vitro engulfment assay using purified astrocytes and synaptosomes. Based on imaging methods, either fluorescent or pH indicator-conjugated synaptosomes can be used in this assay.


Assuntos
Astrócitos/fisiologia , Bioensaio , Fagocitose , Sinaptossomos , Animais , Técnicas de Cultura de Células , Células Cultivadas , Genes Reporter , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Knockout , Microscopia Confocal , Imagem Molecular , Fagócitos , Proteólise , Sinapses
5.
J Vis Exp ; (132)2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29443098

RESUMO

Astrocytes are the major cell type in the brain and directly contact synapses and blood vessels. Although microglial cells have been considered the major immune cells and only phagocytes in the brain, recent studies have shown that astrocytes also participate in various phagocytic processes, such as developmental synapse elimination and clearance of amyloid beta plaques in Alzheimer's disease (AD). Despite these findings, the efficiency of astrocyte engulfment and degradation of their targets is unclear compared with that of microglia. This lack of information is mostly due to the lack of an assay system in which the kinetics of astrocyte- and microglia-mediated phagocytosis are easily comparable. To achieve this goal, we have developed a long-term live-imaging in vitro phagocytosis assay to evaluate the phagocytic capacity of purified astrocytes and microglia. In this assay, real-time detection of engulfment and degradation is possible using pH indicator-conjugated synaptosomes, which emit bright red fluorescence in acidic organelles, such as lysosomes. Our novel assay provides simple and effective detection of phagocytosis through live-imaging. In addition, this in vitro phagocytosis assay can be used as a screening platform to identify chemicals and compounds that can enhance or inhibit the phagocytic capacity of astrocytes. As synaptic pruning malfunction and pathogenic protein accumulation have been shown to cause mental disorders or neurodegenerative diseases, chemicals and compounds that modulate the phagocytic capacity of glial cells should be helpful in treating various neurological disorders.


Assuntos
Astrócitos/metabolismo , Fagocitose/imunologia , Sinaptossomos/metabolismo , Animais , Humanos , Camundongos Transgênicos
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