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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 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.

SUBMITTER: Chen C

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

REPOSITORIES: biostudies-literature

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

Chen Chun C Ahn Eun H EH Liu Xia X Wang Zhi-Hao ZH Luo Shilin S Liao Jianming J Ye Keqiang K

ACS chemical neuroscience 20210609 13

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 ...[more]

PMID: 34106682

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Project description:BackgroundCurrently, there is no cure for Alzheimer's disease (AD). Therapeutics that can modify the early stage of AD are urgently needed. Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase (AEP). Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD. However, more than 90% of AD cases are age-related sporadic AD rather than hereditary AD. The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown.MethodsThe senescence-accelerated mouse prone 8 (SAMP8) was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,: δ-secretase inhibitor 11. Activation of AEP was determined by enzymatic activity assay. Concentration of soluble amyloid β (Aβ) in the brain was determined by ELISA. Morris water maze test was performed to assess the learning and memory-related cognitive ability. Pathological changes in the brain were explored by morphological and western blot analyses.ResultsThe enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the age-matched SAMR1 mice. The half maximal inhibitory concentration (IC50) for δ-secretase inhibitor 11 to inhibit AEP in vitro is was around 150 nM. Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity, reduced the generation of Aβ1-40/42 and ameliorated memory loss. The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation, but also attenuated neuroinflammation in the form of microglial activation. Moreover, treatment with δ-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain.ConclusionsPharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD. The up-regulated AEP in the brain could be a promising target for early treatment of AD. The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.

Dataset Information

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

Publications

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

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