Actions of the TrkB Agonist Antibody ZEB85 in Regulating the Architecture and Synaptic Plasticity in Hippocampal Neurons

Abstract

Signaling of BDNF via its TrkB receptor is crucial in regulating several critical aspects of the architecture and function of neurons both during development and in the adult central nervous system. Indeed, several neurological conditions, such as neurodevelopmental and neurodegenerative disorders are associated with alterations both in the expression levels of BDNF and TrkB, and in their intracellular signaling. Thus, the possibility of promoting BDNF/TrkB signaling has become relevant as a potential therapeutic intervention for neurological disorders. However, the clinical potential of BDNF itself has been limited due to its restricted diffusion rate in biological tissue, poor bioavailability and pharmacological properties, as well as the potential for unwanted side effects due to its ability to also signal via the p75NTR pathway. Several small molecule and biologic drug candidate TrkB agonists have been developed and are reported to have effects in rescuing both the pathological alterations and disease related symptoms in mouse models of several neurological diseases. However, recent side-by-side comparative studies failed to show their specificity for activating TrkB signaling cascades, suggesting the need for the generation and validation of improved candidates. In the present study, we examine the ability of the novel, fully human TrkB agonist antibody ZEB85 to modulate the architecture, activity and synaptic plasticity of hippocampal murine neurons under physiological conditions. Moreover, we show here that ZEB85 prevents β-amyloid toxicity in cultured hippocampal neurons, in a manner which is comparable to BDNF.

BDNF/TrkB signaling endosomes in axons coordinate CREB/mTOR activation and protein synthesis in the cell body to induce dendritic growth in cortical neurons

“…Some vesicles contained both marks and others had one or the other ( Figure 6A ). Then, we performed experiments to find colocalization of f-BDNF vesicles with active TrkB in cell bodies using a commercial phospho- antibody against phospho-tyrosines 706/707 (Y706/707) located in the catalytic domain of the intracellular portion of TrkB ( Tacke et al, 2022 ). We found consistent colocalization of f-BDNF with pTrkB in vesicles larger than 10 µm 2 in the cell body ( Figure 6C, D and H ) and MAP2-positive dendrites ( Figure 6E, F and H ).…”

Effect of Cryptotanshinone on BDNF/TrkB Pathway in Hippocampus of Chronic Stress-induced Depression Rats

“…However, long-term antidepressant administration normalizes BDNF expression in the hippocampus (Han et al, 2020). BDNF-specific receptor TrkB binds to it, further dimerizes and phosphorylates tyrosine residues, triggering intracellular cascade reactions and activating downstream signaling pathways (Tacke et al, 2022), causing up-regulation of synaptic-related protein expression and promoting synaptogenesis (Zhang et al, 2016).…”

Targeting brain‐derived neurotrophic factor in the treatment of neurodegenerative diseases: A review

“…127 The fully human TrkB agonist antibody ZEB85 can protect cultured hippocampal neurons from β-amyloid toxicity and prevent long-term delayed impairments observed in BDNF heterozygous gene-knockout mice. [128][129][130] Compared with BDNF, TrkB-agoAb can induce longer activation of TrkB and reduce TrkB internalization and intracellular degradation, with one TrkB-agoAb increasing the viability of motor neurons in a spinal root avulsion model. 130,131 AS86 is a specific TrkB-activating antibody that does not affect p75 NTR and has been demonstrated to salvage object recognition memory deficits in APP/ PS1 mouse models and reverse spatial memory deficits in 11-month-old AD mouse models.…”

“…Qian et al discovered five mouse monoclonal antibodies that exhibit high selectivity for binding to TrkB, inducing strong activation of TrkB signaling without binding to p75 NTR 127 . The fully human TrkB agonist antibody ZEB85 can protect cultured hippocampal neurons from β‐amyloid toxicity and prevent long‐term delayed impairments observed in BDNF heterozygous gene‐knockout mice 128–130 . Compared with BDNF, TrkB‐agoAb can induce longer activation of TrkB and reduce TrkB internalization and intracellular degradation, with one TrkB‐agoAb increasing the viability of motor neurons in a spinal root avulsion model 130,131 .…”