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Download fileOptimized TrkB Agonist Ameliorates Alzheimer’s Disease Pathologies and Improves Cognitive Functions via Inhibiting Delta-Secretase
journal contribution
posted on 09.06.2021, 20:13 authored by Chun Chen, Eun H. Ahn, Xia Liu, Zhi-Hao Wang, Shilin Luo, Jianming Liao, Keqiang YeBDNF/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.
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via akt phosphorylationpromising preclinical candidateprevious works supportneural synaptic plasticityalleviates cognitive dysfunctionstrkb neurotropic pathwayincluding oral bioavailabilitypromotes ad pathologiesattenuates ad pathologiessynthetic derivative cfdevastating neurodegenerative disease3 </ subcn blocks deltadisease pathologiesad ).trkb lrmoral administrationinhibiting deltasimultaneously cleavesprimary neuronsmouse brainslead compounddownstream signalingdependent proteasedemonstrable toxicitycurrent studycrucial agecn revealscn representschronic treatmentcc2 domain