Journal
THERANOSTICS
Volume 10, Issue 15, Pages 6854-6874Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.44165
Keywords
Neurodegeneration; Therapy; Cognition; Antibody drug; Synaptic plasticity
Categories
Funding
- National Key Research and Development Program of China [2017YFE0126500]
- National Natural Science Foundation of China [81501105, 81861138013, 31730034]
- Beijing Advanced Innovation Center for Human Brain Protection, Shenzhen Science Technology and Innovation Commission [JCYJ20170 411152419928, JCYJ20180508152240368]
- Beijing Municipal Science & Technology Commission [Z151100003915118]
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Repeated failures of A beta-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. Method: Biochemical, electrophysiological and behavioral techniques were used to investigate the effects of AS86 in vitro and in vivo. Results: AS86 specifically activated the BDNF receptor TrkB and its downstream signaling, without affecting its other receptor p75(NTR). It promoted neurite outgrowth, enhanced spine growth and prevented A beta-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. Conclusion: These results demonstrate the potential of AS86 in AD therapy, suggesting that neuronal and/or synaptic repair as an alternative therapeutic strategy for AD.
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