GADD34 suppresses eIF2α phosphorylation and improves cognitive function in Alzheimer's disease-model mice
GADD34 suppresses eIF2α phosphorylation and improves cognitive function in Alzheimer's disease-model mice
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GADD34 抑制 eIF2α 磷酸化并改善阿尔茨海默病模型小鼠的认知功能
DOI：
10.1016/j.bbrc.2023.02.077
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发表时间：
2023
影响因子：
3.1
通讯作者：
Masanori Itoh
中科院分区：
文献类型：
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作者：
Miki Hayakawa-Ogura;Tana;Toshiyuki Nakagawa;Masanori Itoh
阿尔茨海默病（AD）引起神经变性，导致认知障碍和记忆丧失。我们的前期研究表明，槲皮素对生长停滞和DNA损伤诱导基因34（GADD 34）的诱导作用可以影响真核生物翻译起始因子2α（eIF 2 α）磷酸化激活转录因子4（ATF 4）信号通路。然而，GADD 34表达与认知功能的关系尚未阐明。在这项研究中，我们确定了GADD 34对记忆的直接影响。为了实现这一点，将截短的GADD 34（GADD 34.5）注射到小鼠脑中以抑制eIF 2 α磷酸化并评估记忆。海马内注射GADD 34.5不能提高AD模型小鼠对新物体的识别能力，但能提高新物体的定位能力。杏仁核内注射GADD 34.5后，在恐惧条件下，也能维持情境性恐惧记忆。这些结果表明，GADD 34通过抑制eIF 2 α磷酸化有效改善AD患者的空间认知记忆和情境恐惧条件反射。总之，GADD 34抑制大脑中eIF2α的磷酸化并防止记忆丧失。由于槲皮素喂养增加了GADD 34的表达，它可能被用于预防AD。
Alzheimer's disease (AD) causes neurodegeneration, leading to cognitive impairment and memory loss. Our previous studies have demonstrated that the induction of growth arrest and DNA damage-inducible gene 34 (GADD34) by quercetin can affect eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-activated transcription factor 4 (ATF4) signaling. However, the relationship between GADD34 expression and cognitive function has not been clarified. In this study, we determined the direct effect of GADD34 on memory. To achieve this, truncatedGADD34(GADD34.5) was injected into the mouse brain to suppress eIF2α phosphorylation and evaluate memory. The injection ofGADD34.5into the hippocampus in AD-model mice did not improve novel object recognition but improved novel object location. The injection ofGADD34.5into the amygdala also resulted in the maintenance of contextual fear memory based on the fear condition test. These results suggest that GADD34 is effective in improving memory for spatial cognition and contextual fear conditioning in AD by inhibiting eIF2α phosphorylation. In summary, GADD34 suppresses eIF2α phosphorylation in the brain and prevents memory loss. As quercetin feeding increases GADD34 expression, it might be used in preventative applications for AD.