Abstract
Synaptic loss in the brain correlates well with disease severity in Alzheimer disease (AD). Deficits in brain-derived neurotrophic factor/tropomyosin-receptor-kinase B (TrkB) signaling contribute to the synaptic dysfunction of AD. We have recently identified 7,8-dihydroxyflavone (7,8-DHF) as a potent TrkB agonist that displays therapeutic efficacy toward various neurological diseases. Here we tested the effect of 7,8-DHF on synaptic function in an AD model both in vitro and in vivo. 7,8-DHF protected primary neurons from Aβ-induced toxicity and promoted dendrite branching and synaptogenesis. Chronic oral administration of 7,8-DHF activated TrkB signaling and prevented Aβ deposition in transgenic mice that coexpress five familial Alzheimer’s disease mutations (5XFAD mice). Moreover, 7,8-DHF inhibited the loss of hippocampal synapses, restored synapse number and synaptic plasticity, and prevented memory deficits. These results suggest that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating AD.
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Acknowledgements
This work was supported by a grant from the National Institute of Health (RO1, DC010204) to K Ye, the NIH/NIAP50 ADRC center grant to both K Ye and D Weinshenker, and a grant from the National Natural Science Foundation of China (No. 81100958) to Z Zhang.
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Zhang, Z., Liu, X., Schroeder, J. et al. 7,8-Dihydroxyflavone Prevents Synaptic Loss and Memory Deficits in a Mouse Model of Alzheimer’s Disease. Neuropsychopharmacol 39, 638–650 (2014). https://doi.org/10.1038/npp.2013.243
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DOI: https://doi.org/10.1038/npp.2013.243
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