Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity
| Autor: | 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 |
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| Rok vydání: | 2022 |
| Předmět: |
Aging
Amyloid beta-Peptides Membrane Glycoproteins Brain-Derived Neurotrophic Factor Membranes Artificial Cell Biology Neuroblastoma Phosphatidylinositol 3-Kinases Neuroprotective Agents Proto-Oncogene Proteins c-bcl-2 Alzheimer Disease Coumarins Humans Receptor trkB Extracellular Signal-Regulated MAP Kinases Wortmannin Proto-Oncogene Proteins c-akt |
| Zdroj: | Aging. 14(18) |
| ISSN: | 1945-4589 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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