Molecular mechanisms of the BDNF activity in modulating neuronal structure

• Applicants: Professor Dr. Martin Korte; Dr. Marta Zagrebelsky
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 218356167

Strong evidence indicates a role for BDNF/TrkB signaling in modulating activity-dependent structural and functional plasticity at synapses of the central nervous system (CNS). However, the cellular and molecular mechanisms mediating the effects of BDNF signaling remain largely unknown. Moreover, several reports identify alterations in BDNF signaling either as a cause or as a consequence of several neurological illnesses including neurodegenerative diseases (i.e. Alzheimer disease) and thus indicate BDNF as a promising therapeutic agent. However, a poor therapeutic efficiency still limits its use. The possibility of using drugs acting on the endogenous signaling pathways to either modulate the levels of endogenous BDNF or to influence TrkB receptor signaling is of extreme interest, both for better addressing their role in the mature CNS under physiological conditions, and as a possible therapeutic approach for different neurological diseases.The first aim of this grant application takes advantage of the drug Fingolimod, known to cross the blood brain barrier and promote BDNF synthesis from cells in the CNS and of newly developed TrkB agonist antibodies to analyze their ability to modulate neuronal architecture, synaptic transmission and plasticity of mature intact hippocampal neurons in a BDNF-dependent manner. The second aim is to assess the efficacy of a treatment with Fingolimod or with TrkB agonist antibodies in preventing or rescuing some of the most prominent pathological (neuronal architecture, synaptic transmission and plasticity) and behavioral (learning impairment and memory loss) alterations observed in an animal model for Alzheimer disease. With the work envisioned in the current grant application, we plan to characterize the actions on intact mature hippocampal neurons by two approaches to modulate BDNF-TrkB signaling, either by promoting BDNF release or by enhancing TrkB activation. Hereby we will expand the current knowledge on how this pathway is involved in plasticity processes in the intact CNS. Moreover, we will test the therapeutic potential of these two approaches using a mouse model for Alzheimer disease.

• DFG Programme: Research Grants