Abstract
BDNF/TrkB neurotropic pathway, essential for neural synaptic plasticity and survival, is deficient in neurodegenerative diseases including Alzheimer's disease (AD). Our previous works support that BDNF diminishes AD pathologies by inhibiting delta-secretase, a crucial age-dependent protease that simultaneously cleaves both APP and Tau and promotes AD pathologies, via Akt phosphorylation. Small molecular TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) binds and activates the receptor and its downstream signaling, exerting therapeutic efficacy toward AD. In the current study, we optimize 7,8-DHF pharmacokinetic characteristics via medicinal chemistry to obtain a synthetic derivative CF3CN that interacts with the TrkB LRM/CC2 domain. CF3CN possesses improved druglike features, including oral bioavailability and half-life, compared to those of the lead compound. CF3CN activates TrkB neurotrophic signaling in primary neurons and mouse brains. Oral administration of CF3CN blocks delta-secretase activation, attenuates AD pathologies, and alleviates cognitive dysfunctions in 5xFAD. Notably, chronic treatment of CF3CN reveals no demonstrable toxicity. Hence, CF3CN represents a promising preclinical candidate for treating the devastating neurodegenerative disease.