1. Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination
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Ralf A. Linker, Alexander Flügel, De-Hyung Lee, Anne-Christine Flach, Fred Lühder, Eva Geyer, Klaus Jung, and Ralf Gold
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Central Nervous System ,Male ,Encephalomyelitis, Autoimmune, Experimental ,Primary Cell Culture ,Neuroimmunology ,Clinical Neurology ,Neurotrophins ,BDNF ,EAE ,Conditional knock-out mice ,Neuroprotection ,Pathology and Forensic Medicine ,03 medical and health sciences ,Myelin ,Mice ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neurotrophic factors ,medicine ,Animals ,030304 developmental biology ,Brain-derived neurotrophic factor ,Mice, Knockout ,0303 health sciences ,Original Paper ,biology ,Brain-Derived Neurotrophic Factor ,Experimental autoimmune encephalomyelitis ,medicine.disease ,Oligodendrocyte ,Axons ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,nervous system ,Radiation Chimera ,Immunology ,Nerve Degeneration ,biology.protein ,Female ,Neurology (clinical) ,Medicine & Public Health ,Neurosciences ,Pathology ,030217 neurology & neurosurgery ,Neurotrophin - Abstract
Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS), bioactive BDNF is also expressed in immune cells and in lesions of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Previous data revealed that BDNF exerts neuroprotective effects in myelin oligodendrocyte glycoprotein-induced EAE. Using a conditional knock-out model with inducible deletion of BDNF, we here show that clinical symptoms and structural damage are increased when BDNF is absent during the initiation phase of clinical EAE. In contrast, deletion of BDNF later in the disease course of EAE did not result in significant changes, either in the disease course or in axonal integrity. Bone marrow chimeras revealed that the deletion of BDNF in the CNS alone, with no deletion of BDNF in the infiltrating immune cells, was sufficient for the observed effects. Finally, the therapeutic effect of glatiramer acetate, a well-characterized disease-modifying drug with the potential to modulate BDNF expression, was partially reversed in mice in which BDNF was deleted shortly before the onset of disease. In summary, our data argue for an early window of therapeutic opportunity where modulation of BDNF may exert neuroprotective effects in experimental autoimmune demyelination. peerReviewed
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