Indole and Coumarin Derivatives Targeting EEF2K in Aβ Folding Reporter Cells
Shun-Tzu Chi1, Pei-Cih Wei2, Ya-Jen Chiu1
1School of Life Science, National Taiwan Normal University, Taipei, Taiwan.
Journal of Neurochemistry
|January 4, 2025
Summary
New indole and coumarin compounds show promise for Alzheimer's disease treatment by reducing amyloid-beta misfolding and protecting neurons through eukaryotic elongation factor 2 signaling pathways.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Alzheimer's disease (AD) involves amyloid-beta (Aβ) misfolding and neuronal loss.
- This is linked to reduced eukaryotic elongation factor 2 (EEF2) protein synthesis signaling.
Purpose of the Study:
- Investigate neuroprotective effects of indole and coumarin derivatives on Aβ folding and EEF2 signaling.
- Assess compound impact on Aβ-green fluorescent protein (GFP) reporter cells.
Main Methods:
- Utilized SH-SY5Y cells expressing an Aβ-GFP folding reporter.
- Screened indole and coumarin derivatives for effects on Aβ misfolding, reactive oxygen species (ROS), and EEF2 signaling pathways.
- Analyzed effects on acetylcholinesterase, caspase activity, neurite outgrowth, and key protein phosphorylation (ERK, AMPK, EEF2K, EEF2, CREB).
Main Results:
- Two indole (NC009-1, -6) and two coumarin (LM-021, -036) derivatives reduced Aβ misfolding and ROS.
- These compounds decreased acetylcholinesterase and caspase activities, promoting neurite outgrowth.
- Compounds modulated EEF2K/EEF2 signaling, increased CREB phosphorylation, boosted BDNF expression, and reduced BAX/BCL2 ratio, effects dependent on EEF2.
Conclusions:
- Indole and coumarin derivatives (NC009-1, LM-021, LM-036) demonstrate significant neuroprotective potential against AD pathology.
- Therapeutic effects are mediated via modulation of the EEF2K signaling pathway.
- These compounds represent promising candidates for novel Alzheimer's disease therapies.
