LAUSR

Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. This study investigated the neuroprotective effects of indole and coumarin derivatives on Aβ folding and EEF2 signaling using SH‐SY5Y cells expressing Aβ‐green fluorescent protein (GFP) folding reporter. Among the tested compounds, two indole (NC009‐1, ‐6) and two coumarin (LM‐021, ‐036) derivatives effectively reduced Aβ misfolding and associated reactive oxygen species (ROS) production. Additionally, these compounds decreased acetylcholinesterase and caspase‐3/‐6 activities while promoting neurite outgrowth. NC009‐1 increased active phosphorylation of extracellular‐signal regulated kinase (ERK) (T202/Y204), leading to an increase in inactive eukaryotic elongation factor 2 kinase (EEF2K) phosphorylation (S366). LM‐021 decreased the active phosphorylation of AMP‐activated protein kinase (AMPK) (T172) and EEF2K (S398), while LM‐036 exhibited dual effects, increasing inactive phosphorylation and decreasing active phosphorylation of EEF2K. These changes in EEF2K phosphorylation led to decreased EEF2K activity and a subsequent reduction in inactive phosphorylation of EEF2 (T56). This cascade further promoted the phosphorylation of transcription factor cAMP‐response‐element binding protein (CREB) (S133) and the expression of brain‐derived neurotrophic factor (BDNF), and reduced BCL‐2 associated X‐protein (BAX)/B‐cell lymphoma 2 (BCL2) ratio. Knockdown of EEF2 abolished the effects of NC009‐1, LM‐021, and LM‐036 on CREB phosphorylation, BDNF expression, caspase‐3 activity, and neurite outgrowth. These findings demonstrate that NC009‐1, LM‐021, and LM‐036 exert their neuroprotective effects through modulation of EEF2K signaling, highlighting their potentials as therapeutic candidates for AD.