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

This project aims at showing mechanisms of neurodegeneration in Alzheimer's and Huntington's Disease. The focus is on perturbation in mechanisms of synaptic plasticity. The neurotrophic factor BDNF functions in synaptic plasticity and maintenance of synaptic connections, and its function is perturbed in several neurodegenerative conditions. A major target of BDNF signaling in neurons is the protein Arc. A major goal is to determine how Arc signaling is disturbed and how normal function of BDNF and Arc can be restored by drug treatments as well as exercise, using mouse disease models. In the past three years we have obtained data on the regulation of protein synthesis activity and Arc signaling activity in transgenic Alzheimer's model mice. In addition, together with JPND project partners at U. Helsinki, we have obtained new insights on how antidepressant drugs work.

The CircProt JPND is new European axis for tackling mechanisms of degeneration in Huntington?s disease and Alzheimer's disease. New synergies were created, as several of the partners had not worked together before. There was sharing of advance technologies and know-how on evaluation of the animal models and cell-based based studies. The effect of the project is an evaluation of the role of BDNF as a mediator of neuroprotection, and the role signaling mechanism downstream of the BDNF receptor, TrkB.

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 TrkB sig-nalling 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 of BDNF/TrkB downstream signalling networks in NDs. Members of this multidisciplinary research team have recently identified key 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. Advanced molecular imaging, synapse electrophy¬siology, biochemistry, and beha¬vioral testing combined with realistic neural network modeling, will be used to determine optimal therapeutic strategies. This innovative research approach aims to harness the long-recognized therapeutic potential of BDNF, with potentially enormous benefit to people afflicted by neu¬rodegenerative disorders. The parallel analysis of AD and HD associated synaptic circuit dysfunctions and its drug-induced rescue will help us identify common and divergent cellular pathways.