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Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons38948

Krumbholz,  Markus
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons38897

Hohlfeld,  Reinhard
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons38991

Meinl,  Edgar
Department: Neuroimmunology / Wekerle, MPI of Neurobiology, Max Planck Society;

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Citation

Colombo, E., Cordiglieri, C., Melli, G., Newcombe, J., Krumbholz, M., Parada, L. F., et al. (2012). Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration. JOURNAL OF EXPERIMENTAL MEDICINE, 209(3), 521-535. doi:10.1084/jem.20110698.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000F-9CF6-E
Abstract
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.