Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity

Ya Jen Chiu, Te Hsien Lin, Kuo Hsuan Chang, Wenwei Lin, Hsiu Mei Hsieh-Li, Ming Tsan Su, Chiung Mei Chen*, Ying Chieh Sun*, Guey Jen Lee-Chen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer’s disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood–brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD.

Original languageEnglish
Pages (from-to)7568-7586
Number of pages19
Issue number18
Publication statusPublished - 2022


  • Alzheimer’s disease
  • Neuroprotection
  • Therapeutics
  • Trkb agonists

ASJC Scopus subject areas

  • Ageing
  • Cell Biology


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