CNS neuroscience & therapeutics · 2026
Betulinaldehyde Ameliorates Aβ-Induced Neurotoxicity and Cognitive Deficits by Modulating the eEF2K/eEF2 Pathway.
СтатьяНазвание и аннотация: Перевод в очереди
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Wang Chaoqun, Han Xiaohe, Lin Yali, Pan Yan, Miao Qiuping, Wang Yaping, Wang Shu-Qin, Zhang Zhu, Wang Luyao, Tang Zhi-Ri, Peng Yinghui, Yung Ken Kin-Lam, Ma Nan, Lu Dan, Zhang Shiqing, Shi Lei
Аннотация
BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, remains without effective therapies. Dysregulated eukaryotic elongation factor 2 kinase/eukaryotic elongation factor 2 (eEF2K/eEF2) pathway leads to aberrant protein synthesis and impaired neuronal function in AD, positioning this axis as a promising therapeutic target. However, effective pharmacological modulators of eEF2K/eEF2 remain limited. Betulinaldehyde (Betu), an active ingredient derived from traditional Chinese medicine, remains to be thoroughly evaluated as a potential neuroprotective agent.
PURPOSE: This study aims to investigate the therapeutic effects of Betu on AD and determine whether its activities are mediated through the eEF2K/eEF2 pathway.
METHODS: Neuronal cell models were used to assess the effects of Betu on β-amyloid 42 (Aβ42)-induced neuronal death, dendritic spine damage, protein synthesis inhibition, and eEF2 hyperphosphorylation. The eEF2K agonist nelfinavir (NFV) and the protein synthesis inhibitors cycloheximide (CHX) and anisomycin (AS) were used to investigate the involvement of the eEF2K/eEF2 pathway and its regulated protein synthesis in the action of Betu. The cellular thermal shift assay (CETSA) was used to detect potential interactions between Betu and eEF2K. Additionally, the effects of Betu on reactive oxygen species (ROS) levels and the associated pathways were evaluated. An Aβ42-induced mouse model of AD was used to evaluate the in vivo effects of Betu on cognitive decline, hippocampal neuropathological damage, and eEF2 hyperphosphorylation.
RESULTS: Betu significantly ameliorated the Aβ42-induced neuronal death and dendritic spine damage, restored protein synthesis, and reversed eEF2 hyperphosphorylation. The neuroprotective effects of Betu were effectively inhibited by the CHX, AS, or NFV treatment, and CETSA supported a potential interaction between Betu and eEF2K. Furthermore, Betu reversed Aβ42-induced ROS accumulation and upregulated nuclear factor-like 2 and heme oxygenase-1, potential downstream effectors of the eEF2K pathway. In an Aβ42-induced AD mouse model, Betu treatment markedly ameliorated cognitive decline, concomitant with attenuated neuropathological damage and restored eEF2 phosphorylation in the hippocampus.
CONCLUSION: These findings demonstrate that Betu protects against Aβ42-induced neurotoxicity by modulating the eEF2K/eEF2 pathway, highlighting its potential as a lead compound for AD.
PURPOSE: This study aims to investigate the therapeutic effects of Betu on AD and determine whether its activities are mediated through the eEF2K/eEF2 pathway.
METHODS: Neuronal cell models were used to assess the effects of Betu on β-amyloid 42 (Aβ42)-induced neuronal death, dendritic spine damage, protein synthesis inhibition, and eEF2 hyperphosphorylation. The eEF2K agonist nelfinavir (NFV) and the protein synthesis inhibitors cycloheximide (CHX) and anisomycin (AS) were used to investigate the involvement of the eEF2K/eEF2 pathway and its regulated protein synthesis in the action of Betu. The cellular thermal shift assay (CETSA) was used to detect potential interactions between Betu and eEF2K. Additionally, the effects of Betu on reactive oxygen species (ROS) levels and the associated pathways were evaluated. An Aβ42-induced mouse model of AD was used to evaluate the in vivo effects of Betu on cognitive decline, hippocampal neuropathological damage, and eEF2 hyperphosphorylation.
RESULTS: Betu significantly ameliorated the Aβ42-induced neuronal death and dendritic spine damage, restored protein synthesis, and reversed eEF2 hyperphosphorylation. The neuroprotective effects of Betu were effectively inhibited by the CHX, AS, or NFV treatment, and CETSA supported a potential interaction between Betu and eEF2K. Furthermore, Betu reversed Aβ42-induced ROS accumulation and upregulated nuclear factor-like 2 and heme oxygenase-1, potential downstream effectors of the eEF2K pathway. In an Aβ42-induced AD mouse model, Betu treatment markedly ameliorated cognitive decline, concomitant with attenuated neuropathological damage and restored eEF2 phosphorylation in the hippocampus.
CONCLUSION: These findings demonstrate that Betu protects against Aβ42-induced neurotoxicity by modulating the eEF2K/eEF2 pathway, highlighting its potential as a lead compound for AD.