Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration
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- Emanuela Colombo
- Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy 1
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- Chiara Cordiglieri
- Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy 1
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- Giorgia Melli
- Neuroimmunology and Neuromuscular Disorders Unit 2 and 3
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- Jia Newcombe
- NeuroResource, University College London Institute of Neurology, London WC1N 3BG, England, UK 4
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- Markus Krumbholz
- Max Planck Institute of Neurobiology, 82152 Martinsried, Germany 5
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- Luis F. Parada
- Center for Developmental Biology, University of Texas at Dallas, Dallas, TX 75080 7
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- Enzo Medico
- Institute for Cancer Research and Treatment, 10060 Torino, Italy 8
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- Reinhard Hohlfeld
- Max Planck Institute of Neurobiology, 82152 Martinsried, Germany 5
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- Edgar Meinl
- Max Planck Institute of Neurobiology, 82152 Martinsried, Germany 5
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- Cinthia Farina
- Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy 1
説明
<jats:p>Neurotrophin growth factors support neuronal survival and function. In this study, we show that the expression of the neurotrophin receptor TrkB is induced on astrocytes in white matter lesions in multiple sclerosis (MS) patients and mice with experimental autoimmune encephalomyelitis (EAE). Surprisingly, mice lacking TrkB specifically in astrocytes were protected from EAE-induced neurodegeneration. In an in vitro assay, astrocytes stimulated with the TrkB agonist brain-derived neurotrophic factor (BDNF) released nitric oxide (NO), and conditioned medium from activated astrocytes had detrimental effects on the morphology and survival of neurons. This neurodegenerative process was amplified by NO produced by neurons. NO synthesis in the central nervous system during EAE depended on astrocyte TrkB. Together, these findings suggest that TrkB expression on astrocytes may represent a new target for neuroprotective therapies in MS.</jats:p>
収録刊行物
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- Journal of Experimental Medicine
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Journal of Experimental Medicine 209 (3), 521-535, 2012-03-05
Rockefeller University Press