Brain derived neurotrophic factor (BDNF): Untersuchungen zur Expression und Regulation in vitro sowie zur funktionellen Relevanz in der experimentellen autoimmunen Enzephalomyelitis (EAE)

Abstract

The neurotrophin brain derived neurotrophic factor (BDNF) is essential for the development and maintenance of the nervous system. Neurons are the main cellular source of this neurotrophin, but it was also shown that immune cells, e.g. infiltrates in multiple sclerosis lesions, express bioactive BDNF. Several studies proposed that this neurotrophin could mediate neuroprotective effects of immune cells, resulting in the concept of neuroprotective autoimmunity. This concept is based on the assumption that beside of their aggressive and destructive function, autoimmune T cells also exhibit axonprotective properties through the expression of regulatory molecules like BDNF.In the first part of the work, the investigations were focused on the expression of the different splice variants of BDNF mRNA in the cells of the immune system in comparison to cells of the central nervous system. It could be shown that the expression of BDNF splice variants is significantly different in the brain and the immune system, indicating different regulatory mechanisms of BDNF mRNA expression in different cell types, whereas the physiological relevance of the splice variants is still unclear.To study the functional relevance of BDNF in experimental autoimmune encephalomyelitis (EAE), a lentiviral complementation approach was used, where T cells were infected with a lentivirus in which the BDNF cDNA was inserted and injected in mice, in which EAE was induced. Injection of these BDNF overexpressing T cells lead to a diminished EAE course whereas injection of T cells infected with a GFP overexpressing lentivirus had no effect. Additional histological analyses of axonal damage showed lower APP accumulation, iNOS expression and higher axonal preservation in lesions and perilesions of the BDNF treated mice compared to the GFP treated control, which confirmed the clinical observations.Taken together these experiments could clearly show that BDNF has an axonprotective role in EAE, thereby placing BDNF into the focus as a potential therapeutic target in multiple sclerosis or other autoimmune diseases.