Molecular mechanisms of the BDNF activity in modulating neuronal structure

BDNF 活性调节神经元结构的分子机制

• 批准号: 218356167
• 负责人: Professor Dr. Martin Korte
• 金额: --
• 依托单位: Zoologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/218356167?language=en
• 关键词: Molecular; mechanisms; BDNF; activity; modulating

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.

强有力的证据表明BDNF/TrkB信号在调节中枢神经系统（CNS）突触的活性依赖性结构和功能可塑性中的作用。然而，介导BDNF信号传导作用的细胞和分子机制仍然很大程度上未知。此外，一些报道鉴定了BDNF信号传导的改变作为包括神经变性疾病（即阿尔茨海默病）的几种神经系统疾病的原因或结果，因此表明BDNF作为有希望的治疗剂。然而，较差的治疗效果仍然限制了其使用。使用作用于内源性信号传导途径的药物来调节内源性BDNF的水平或影响TrkB受体信号传导的可能性是非常令人感兴趣的，这两种可能性都是为了更好地解决它们在生理条件下在成熟CNS中的作用，并且作为不同神经系统疾病的可能治疗方法。使用已知穿过血脑屏障并促进CNS中细胞的BDNF合成的TrkB激动剂抗体和新开发的TrkB激动剂抗体来分析它们以BDNF依赖性方式调节成熟完整海马神经元的神经元结构、突触传递和可塑性的能力。第二个目的是评估用芬戈莫德或用TrkB激动剂抗体治疗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学（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）改变中的功效。通过当前拨款申请中设想的工作，我们计划通过两种方法来调节BDNF-TrkB信号传导（通过促进脑源性神经营养因子释放或通过增强TrkB激活）来表征对完整成熟海马神经元的作用。因此，我们将扩大目前的知识，这一途径是如何参与在完整的中枢神经系统的可塑性过程。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。