Optimized TrkB Agonist Ameliorates Alzheimer's Disease Pathologies and Improves Cognitive Functions via Inhibiting Delta-Secretase.

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 druglik

SUBMITTER: Chen C 

PROVIDER: S-EPMC8269693 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature