Endoplasmic reticulum stress/autophagy pathway is involved in diabetes-induced neuronal apoptosis and cognitive decline in mice
Endoplasmic reticulum stress/autophagy pathway is involved in diabetes-induced neuronal apoptosis and cognitive decline in mice
复制标题
内质网应激/自噬通路参与糖尿病诱导的小鼠神经元凋亡和认知能力下降
DOI：
10.1042/cs20171432
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发表时间：
2018-01-16
期刊：
影响因子：
6
通讯作者：
Qu, Shen
中科院分区：
文献类型：
--
作者：
Kong, Fei-Juan;Ma, Lei-Lei;Qu, Shen
糖尿病是一个重大的全球公共卫生问题，其发病率在全球范围内呈上升趋势。作为糖尿病的严重并发症，糖尿病相关认知功能减退日益受到人们的关注。然而，潜在的机制尚未完全确定。内质网应激和自噬都被报道调节神经元的存活和死亡，并与一些神经退行性疾病有关。本研究利用链脲佐菌素诱导的糖尿病小鼠模型和原代培养的小鼠海马神经元，研究内质网应激和自噬在糖尿病诱导的神经细胞凋亡和认知损害中的可能作用，并进一步探讨其潜在的分子机制。内质网应激标志物GRP78和CHOP在糖尿病小鼠中均增强，PERK、IRE1α和JNK的磷酸化也是如此。此外，结果表明糖尿病小鼠的自噬水平升高，表现为自噬标志物LC3-II、BECLIN1的表达上调，p62的表达下调，自噬空泡和LC3-II聚集体的形成增加。同时，我们在体外发现内质网应激抑制剂4-苯基丁酸酯或JNK抑制剂SP600125可消除上述作用。此外，4-苯丁酸酯可减轻糖尿病小鼠神经细胞的凋亡，而自噬抑制剂巴菲霉素A1在体外可加重糖尿病小鼠的神经细胞凋亡。这些结果提示，内质网应激途径可能参与糖尿病所致的神经毒性，并促进以下认知损害。更重要的是，糖尿病可能通过内质网应激介导的JNK途径诱导自噬，这可能保护神经元免受内质网应激相关的细胞损伤。
Diabetes mellitus is a significant global public health problem depicting a rising prevalence worldwide. As a serious complication of diabetes, diabetes-associated cognitive decline is attracting increasing attention. However, the underlying mechanisms are yet to be fully determined. Both endoplasmic reticulum (ER) stress and autophagy have been reported to modulate neuronal survival and death and be associated with several neurodegenerative diseases. Here, a streptozotocin-induced diabetic mouse model and primary cultured mouse hippocampal neurons were employed to investigate the possible role of ER stress and autophagy in diabetes-induced neuronal apoptosis and cognitive impairments, and further explore the potentialmolecular mechanisms. ER stress markers GRP78 and CHOPwere both enhanced in diabetic mice, as was phosphorylation of PERK, IRE1 alpha, and JNK. In addition, the results indicated an elevated level of autophagy in diabetic mice, as demonstrated by up-regulated expressions of autophagy markers LC3-II, beclin 1 and down-regulated level of p62, and increased formation of autophagic vacuoles and LC3-II aggregates. Meanwhile, we found that these effects could be abolished by ER stress inhibitor 4-phenylbutyrate or JNK inhibitor SP600125 in vitro. Furthermore, neuronal apoptosis of diabetic mice was attenuated by pretreatment with 4-phenylbutyrate, while aggravated by application of inhibitor of autophagy bafilomycin A1 in vitro. These results suggest that ER stress pathway may be involved in diabetes-mediated neurotoxicity and promote the following cognitive impairments. More important, autophagy was induced by diabetes possibly through ER stress-mediated JNK pathway, which may protect neurons against ER stress-associated cell damages.