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.

真核起始因子 2 (eIF2α) 通路在阿尔茨海默病中过度激活，可能与突触和记忆缺陷有关。EIF2α 蛋白主要负责调节真核细胞中的蛋白质合成。负责 ser-51 上 eIF2α 磷酸化的四种激酶是：通用控制非去抑制 2 激酶 (GCN2)、双链 RNA 活化蛋白激酶 (PKR)、PKR 样内质网激酶 (PERK) 和血红素调节抑制剂激酶 (HRI) 是四种激酶。它们导致一般翻译水平降低和应激反应性 mRNA 表达的反常增加，包括 B 分泌酶 (BACE1) 和转录调节剂激活转录因子 4 (ATF4)，进而加速 β-淀粉样蛋白生成、tau 磷酸化、促凋亡通路诱导和自噬元件形成导致 AD 的主要病理特征。研究结果表明，相应激酶的遗传或药理学抑制可以恢复记忆并防止神经变性。这意味着通过响应激酶抑制 eIF2α 磷酸化确实是临床应用的可行前景。本综述讨论了最近针对 eIF2α 通路的治疗方法，并概述了相应激酶过度激活与 AD 神经变性之间的联系。这意味着通过响应激酶抑制 eIF2α 磷酸化确实是临床应用的可行前景。本综述讨论了最近针对 eIF2α 通路的治疗方法，并概述了相应激酶过度激活与 AD 神经变性之间的联系。这意味着通过响应激酶抑制 eIF2α 磷酸化确实是临床应用的可行前景。本综述讨论了最近针对 eIF2α 通路的治疗方法，并概述了相应激酶过度激活与 AD 神经变性之间的联系。