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Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity
- Source :
- Aging. 14(18)
- Publication Year :
- 2022
-
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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 19454589
- Volume :
- 14
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- Aging
- Accession number :
- edsair.doi.dedup.....c8b2d49adbac1a8e63d1c9edd06edde4