title: Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration.
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.
authors.affiliation: Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Colombo
authors.forename: Chiara
authors.initials: C
authors.lastname: Cordiglieri
authors.forename: Giorgia
authors.initials: G
authors.lastname: Melli
authors.forename: Jia
authors.initials: J
authors.lastname: Newcombe
authors.forename: Markus
authors.initials: M
authors.lastname: Krumbholz
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.forename: Enzo
authors.initials: E
authors.lastname: Medico
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
authors.forename: Cinthia
authors.initials: C
authors.lastname: Farina
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020813:Receptor, trkB / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D009569:Nitric Oxide; D020813:Receptor, trkB