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Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ
Ya-Jen Chiu1, Te-Hsien Lin1, Kuo-Hsuan Chang2
1Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan.
Abstract:
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.
Insights
New coumarin analogs, LMDS-1 and -2, act as TRKB agonists to protect against Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Decreased Brain-Derived Neurotrophic Factor (BDNF) and impaired Tropomyosin receptor kinase B (TRKB) signaling are implicated in Alzheimer's disease (AD) neurodegeneration.
- Previous research demonstrated that coumarin derivative LM-031 enhances the CREB/BDNF/BCL2 pathway.
Purpose of the Study:
- To investigate if LM-031 analogs (LMDS-1 to -4) function as TRKB agonists.
- To evaluate the neuroprotective potential of LMDS compounds against amyloid-beta (Aβ) toxicity in SH-SY5Y cells.
Main Methods:
- Molecular docking simulations to assess TRKB binding affinity.
- In vitro assays using SH-SY5Y cells with induced Aβ-GFP expression to evaluate neuroprotection and anti-aggregation.
- TRKB knockdown experiments and pharmacological inhibition of downstream signaling pathways (ERK, PI3K-AKT).
- Parallel artificial membrane permeability assay (PAMPA) for blood-brain barrier (BBB) permeability assessment.
Main Results:
- All four LMDS compounds showed potential for binding to domain d5 of TRKB.
- LMDS compounds demonstrated anti-aggregation and neuroprotective effects in Aβ-GFP expressing SH-SY5Y cells.
- TRKB knockdown abrogated the neuroprotective and neurite outgrowth-promoting effects of LMDS compounds.
- LMDS-1 and -2 activate downstream TRKB signaling pathways, including ERK, PI3K-AKT, and CREB.
- LMDS-1 and -2 exhibit blood-brain barrier permeability.
Conclusions:
- LMDS-1 and LMDS-2 likely act as TRKB agonists, exerting neuroprotection in Aβ-toxicity models.
- These compounds activate key downstream signaling pathways, supporting their therapeutic potential for Alzheimer's disease.
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