Therapeutic potential of a TrkB agonistic antibody for Alzheimer's disease

• Published in: Theranostics 2020-01, Vol.10 (15), p.6854-6874
• Main Authors: Wang, Shudan, Yao, Hongyang, Xu, Yihua, Hao, Rui, Zhang, Wen, Liu, Hang, Huang, Ying, Guo, Wei, Lu, Bai
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - immunology; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Animal cognition; Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Apoptosis; Brain; Cells, Cultured; Cognitive ability; Cricetinae; Disease Models, Animal; Experiments; Hippocampus - drug effects; Hippocampus - metabolism; Immunologic Factors - pharmacology; Kinases; Ligands; Long-Term Potentiation; Memory; Mice; Mice, Transgenic; Neuronal Plasticity; Pathogenesis; Pathology; Pathophysiology; Phosphorylation; Proteins; Receptor, trkB - agonists; Receptor, trkB - metabolism; Research Paper; Synapses
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.44165

Repeated failures of "Aβ-lowering" therapies call for new targets and therapeutic approaches for Alzheimer's disease (AD). We propose to treat AD by halting neuronal death and repairing synapses using a BDNF-based therapy. To overcome the poor druggability of BDNF, we have developed an agonistic antibody AS86 to mimic the function of BDNF, and evaluate its therapeutic potential for AD. Biochemical, electrophysiological and behavioral techniques were used to investigate the effects of AS86 and . AS86 specifically activated the BDNF receptor TrkB and its downstream signaling, without affecting its other receptor p75 . It promoted neurite outgrowth, enhanced spine growth and prevented Aβ-induced cell death in cultured neurons, and facilitated Long-Term Potentiation (LTP) in hippocampal slices. A single-dose tail-vein injection of AS86 activated TrkB signaling in the brain, with a half-life of 6 days in the blood and brain. Bi-weekly peripheral administration of AS86 rescued the deficits in object-recognition memory in the APP/PS1 mouse model. AS86 also reversed spatial memory deficits in the 11-month, but not 14-month old AD mouse model. These results demonstrate the potential of AS86 in AD therapy, suggesting that neuronal and/or synaptic repair as an alternative therapeutic strategy for AD.