Abstract
Eukaryotic initiation factor 2 (eIF2α) pathway is overactivated in Alzheimer disease and is probably associated with synaptic and memory deficiencies. EIF2α protein is principally in charge of the regulation of protein synthesis in eukaryotic cells. Four kinases responsible for eIF2α phosphorylation at ser-51 are: General control non-derepressible-2 kinase (GCN2), double-stranded RNA-activated protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), and heme-regulated inhibitor kinase (HRI) are the four kinases. They lead to reduced levels of general translation and paradoxical increase of stress-responsive mRNAs expression including the B-secretase (BACE1) and the transcriptional modulator activating transcription factor 4 (ATF4), which in turn accelerates the beta-amyloidogenesis, tau phosphorylation, proapoptotic pathway induction and autophagy elements formation leading to the main pathological hallmarks of AD. Findings suggest that genetic or pharmacological inhibition of correspondent kinases can restore memory and prevent neurodegeneration. This implies that inhibition of eIF2α phosphorylation through respondent kinases is indeed a feasible prospect of clinical application. This review discusses recent therapeutic approaches targeting eIF2α pathway and provides an overview of the links between correspondent kinases overactivation with neurodegeneration in AD.
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Highlights
• Chronic phosphorylation of eIF2α pathway due to correspondent kinases overactivation is harmful to neuronal plasticity and memory formation.
• Genetic or pharmacological inhibition of eIF2α pathway activity can restore memory and prevent neurodegeneration.
• Gastrodin is capable of Suppressing BACE1 expression under oxidative stress condition via inhibition of the PKR/eIF2α signaling pathway in AD.
• BACE1 translation is regulated by NO through HRI.
• Fine-tuning the eIF2α inhibition genetically or by using the repurposed drugs like Trazodone or dibenzoylmethane (DBM) can be a promising therapeutic target for AD.
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Moradi Majd, R., Mayeli, M. & Rahmani, F. Pathogenesis and promising therapeutics of Alzheimer disease through eIF2α pathway and correspondent kinases. Metab Brain Dis 35, 1241–1250 (2020). https://doi.org/10.1007/s11011-020-00600-8
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DOI: https://doi.org/10.1007/s11011-020-00600-8