CircProt: Synaptic circuit protection in AD and HD: BDNF/TrkB and Arc signaling as rescue factors

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. 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.