Molecular mechanisms of the BDNF activity in modulating neuronal structure

强有力的证据表明，BDNF/TrkB信号在调节中枢神经系统(CNS)突触的活性依赖的结构和功能可塑性方面发挥了作用。然而，BDNF信号转导的细胞和分子机制仍然很大程度上是未知的。此外，一些报告发现BDNF信号的改变是包括神经退行性疾病(即阿尔茨海默病)在内的几种神经系统疾病的原因或结果，因此表明BDNF是一种有前途的治疗剂。然而，较差的治疗效率仍然限制了它的使用。使用作用于内源性信号通路的药物来调节内源性BDNF的水平或影响TrkB受体信号的可能性是人们非常感兴趣的，这既是为了更好地解决它们在生理条件下在成熟的CNS中的作用，也是作为一种可能的治疗方法来治疗不同的神经疾病。这项拨款申请的第一个目的是利用药物Fingolimod和新开发的TrkB激动剂抗体来分析它们以BDNF依赖的方式调节成熟的完整海马神经元的神经元结构、突触传递和可塑性的能力。Fingolimod已知可以跨越血脑屏障并促进CNS细胞合成BDNF。第二个目的是评估Fingolimod或TrkB激动剂抗体在预防或挽救在阿尔茨海默病动物模型中观察到的一些最显著的病理(神经元结构、突触传递和可塑性)和行为(学习障碍和记忆丧失)改变方面的疗效。根据目前的GRANT申请中设想的工作，我们计划通过两种方法来调节BDNF-TrkB信号，或者通过促进BDNF的释放，或者通过增强TrkB的激活，来表征对完整成熟海马神经元的作用。因此，我们将扩展目前关于这一途径如何参与完整中枢神经系统的可塑性过程的知识。此外，我们将使用阿尔茨海默病的小鼠模型来测试这两种方法的治疗潜力。

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.