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Synaptic circuit protection in AD and HD: BDNF/TrkB and Arc signaling as rescue factors
EU - ERA Net, Joint Programm;
Regulation of synaptic plasticity by brain-derived neurotrophic factor (BDNF) is crucial for brain function, as it pilots adaptive changes in neural networks. Pathological changes in BDNF availability and tropomyo­sine related kinase (TrkB) sig­naling are therefore among the most relevant pathomechanisms in neurode­gene­rative disorders (NDs). Huntington´s disease (HD) and Alzheimer´s disease (AD) are both strongly associated with BDNF related impairments. While BDNF is recognized as an endogenous protective factor in both diseases, the development of  therapeutic strategies has been hampered by the lack of knowledge on BDNF transport and release, and on BDNF/TrkB downstream signaling networks in NDs. Members of this multidisciplinary research consortium have recently discovered key complex molecular controls of major importance for therapeutics, including the immediate early protein Arc, as a master hub for functional and structural synaptic plasticity (Fig.1). Building on these breakthroughs, we propose that BDNF/TrkB signaling via Arc function is key for the management and treat­­ment of synaptic dys­func­tion and neuronal degeneration in AD and HD. This project will identify novel combinatorial and synergistic strategies to alleviate AD and HD related impair­ments based on regulation of TrkB and its downstream signaling cascades. As an important upstream regulator, mobilization of endogenous BDNF synthesis and its transport will be given additional emphasis. Key protec­tive factors are activa­tion of neu­ro­nal burst firing in brain areas affected by the disease com­bined with physical exercise, and appli­cation of drugs that enhance BDNF ex­pres­sion (fingo­limod) or BDNF vesicle trans­port (tubasta­tin and cysteamine). Advanced mol­ecu­lar imaging, synapse elec­tro­phy­siology, bio­che­mistry, and be­ha­vioral testing combined with rea­listic neural network modeling, will be used to deter­mine opti­mal the­rapeutic stra­te­gies. This high­­ly innovative re­search ap­proach aims to har­ness the well-recog­nized thera­peu­tic potential of BDNF, with potentially enor­mous benefit to people afflicted by NDs. The parallel analysis of AD and HD associated synaptic cir­cuit dys­func­tions and its drug-induced rescue will help us to identify common and divergent cel­lular path­ways. Fur­ther­more, know­ledge of brain area-specific me­cha­nisms and drug effects will enable us to target most spe­ci­fically the diffe­rent NDs with re­duced side ef­fects. By com­bining advanced molecular and electro­physiological studies of drug-in­duced improved synaptic plasticity with computational modeling of restored synaptic circuits, we expect to elucidate novel therapeutic mechanisms downstream of BDNF/TrkB signaling, with clear benefit for the treatment of AD and HD.


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