Central nervous system rather than immune cell-derived BDNF mediates axonal protective effects early in autoimmune demyelination.
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.
Department of Neurology, Friedrich-Alexander University Erlangen, Germany.
De-Hyung
DH
Lee
Eva
E
Geyer
Anne-Christine
AC
Flach
Klaus
K
Jung
Ralf
R
Gold
Alexander
A
Flügel
Ralf A
RA
Linker
Fred
F
Lühder
D000818:Animals; D001369:Axons / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D011828:Radiation Chimera
D019208:Brain-Derived Neurotrophic Factor