Role of a novel TrkB agonist antibody in positively modulating the architecture and synaptic plasticity of hippocampal neurons in health and disease

Abstract

Brain derived neurotrophic factor (BDNF), signaling via its receptor Tropomyosin receptor kinase B (TrkB) plays a pivotal role in establishing and maintaining the structure and function of neurons within the central nervous system. Deficits in BDNF/TrkB signaling are reported to contribute to the pathogenesis of multiple major disorders, such as Alzheimer’s disease. While manipulating the BDNF/TrkB signaling has been shown to be a viable approach to ameliorate some of the symptoms in a variety of neurological and psychiatric disorders, effective delivery of BDNF into the brain is challenging due to its poor pharmacokinetic profile and clinical translation has fallen short. This triggered the development of BDNF mimetics which specifically activate the TrkB receptor. This work investigated whether a recently identified fully human TrkB agonist antibody (ZEB85) exerts similar biological functions to BDNF. It was shown that treatment with ZEB85 leads to TrkB phosphorylation and increases expression of the activity-dependent immediate early gene c-Fos. Further, ZEB85 significantly increases the neurite complexity of developing hippocampal neurons. Parvalbumin positive interneurons from hippocampal cultures deprived of BDNF have a severely altered dendritic phenotype which can be completely rescued by the TrkB agonist antibody. Moreover, ZEB85 leads to changes in spine number and morphology in mature neurons. Under pathological conditions, treatment with ZEB85 completely prevents amyloid-beta induced dendritic spine loss. Lastly, prolonged application of ZEB85 over several days in hippocampal organotypic slice cultures prepared from heterozygous bdnf knockout mice, known to have deficits in the induction and maintenance of long-term potentiation (LTP) improved these parameters. Taken together, ZEB85 indeed exerts some of the biological functions of BDNF as seen in TrkB activation and structural and functional changes of healthy and diseased neurons. However, when directly compared to BDNF, the effect of ZEB85 is less pronounced. Thus, this work provides an initial characterization of a new promising TrkB agonist suggesting its potential value for therapeutical applications.